Acute Myeloid Leukemia Patient-Derived Xenograft Models Generated with the Use of Immunodeficient NSG-SGM3 Mice

EV Baidyuk1, EV Belotserkovskaya1, LL Girshova1,2, VA Golotin1, KA Levchuk2, ML Vasyutina2, YaA Portnaya1, EV Shchelina2, OG Bredneva2, AV Petukhov1,2,3, AYu Zaritskey2, ON Demidov1,3

1 Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064

2 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

3 Sirius University of Science and Technology, 1 Olimpiiskii pr-t, Sochi, Russian Federation, 354340

For correspondence: Ekaterina Viktorovna Baidyuk, PhD in Biology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064; e-mail: katya_bay@mail.ru; Ekaterina Vasilevna Belotserkovskaya, PhD in Biology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064; e-mail: belotserkovskaya.ev@gmail.com

For citation: Baidyuk EV, Belotserkovskaya EV, Girshova LL, et al. Acute Myeloid Leukemia Patient-Derived Xenograft Models Generated with the Use of Immunodeficient NSG-SGM3 Mice. Clinical oncohematology. 2021;14(4):414–25. (In Russ).

DOI: 10.21320/2500-2139-2021-14-4-414-425


ABSTRACT

Background. Up to the present the survival rates of acute myeloid leukemia (AML) patients have remained low. A successful OML management presupposes generating personalized models of the disease. The most promising research activity in this field is creation of AML patient-derived xenograft models using the advanced strain of immunodeficient humanized NSG-SGM3 mice.

Aim. To generate AML patient-derived xenograft models using immunodeficient NSG-SGM3 mice.

Materials & Methods. The creation of PDX models was based on bone marrow aspirates taken from 4 patients with newly diagnosed AML who were treated at the VA Almazov National Medical Research Center. Patient-derived tumor cells were transplanted to NSG-SGM3 mice. Test experiment consisted in injecting AML cells OCI-АМL2 and HL60 in NSG-SGM3 mice. The efficacy of tumor engraftment was evaluated in terms of physical condition of animals and laboratory tests (blood count, blood smear, PCR, and flow cytofluorometry).

Results. The engraftment of applied tumor cells derived from 4 AML patients was achieved in half (2 out of 4) of the mice. In 2 mice with successful transplantation leukocytosis was reported. Blast cells were identified in peripheral blood on Day 30 after transplantation. The mice with injected AML cells OCI-АМL2 and HL60 showed a more aggressive course of disease. Among tested approaches to evaluate tumor engraftment in mouse recipients, the PCR method was marked by highest sensitivity.

Conclusion. The use of immunodeficient humanized NSG-SGM3 mice enables successful generation of AML patient-derived xenograft models.

Keywords: xenograft model, immunodeficient humanized mice, AML, NSG-SGM3 mice.

Received: April 27, 2021

Accepted: August 1, 2021

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Статистика Plumx английский

REFERENCES

  1. Saultz JN, Garzon R. Acute Myeloid Leukemia: A Concise Review. J Clin Med. 2016;5(3):33. doi: 10.3390/jcm5030033.
  2. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487–94. doi: 10.1200/jco.2010.30.1820.
  3. Patel SA, Gerber JM. A User’s Guide to Novel Therapies for Acute Myeloid Leukemia. Clin Lymphoma Myel Leuk. 2020;20(5):277–88. doi: 10.1016/j.clml.2020.01.011.
  4. Levine RL. Molecular pathogenesis of AML: translating insights to the clinic. Best Pract Res Clin Haematol. 2013;26(3):245–8. doi: 10.1016/j.beha.2013.10.003.
  5. Mitra A, Mishra L, Li S. Technologies for deriving primary tumor cells for use in personalized cancer therapy. Trends Biotechnol. 2013;31(6):347–54. doi: 10.1016/j.tibtech.2013.03.006.
  6. Bruserud О, Gjertsen BT, Foss B, et al. New strategies in the treatment of acute myelogenous leukemia (AML): In vitro culture of AML cells—The present use in experimental studies and the possible importance for future therapeutic approaches. Stem Cells. 2001;19(1):1–11. doi: 10.1634/stemcells.19-1-1.
  7. Ryningen A, Stapnes C, Bruserud О. Clonogenic acute myelogenous leukemia cells are heterogeneous with regard to regulation of differentiation and effect of epigenetic pharmacological targeting. Leuk Res. 2007;31(9):1303–13. doi: 10.1016/j.leukres.2007.01.019.
  8. Непомнящих Т.С., Гаврилова Е.В., Максютов Р.А. Некоторые аспекты использования алло- и ксенографтных моделей при разработке противораковых вакцин и онколитических вирусов. Медицинская иммунология. 2019;21(2):221–30. doi: 10.15789/1563-0625-2019-2-221-230.
    [Nepomnyashchikh TS, Gavrilova EV, Maksyutov RA. Selected aspects of allo- and xenograft model applications for developing novel anti-cancer vaccines and oncolytic viruses. Medical Immunology (Russia). 2019;21(2):221–30. doi: 10.15789/1563-0625-2019-2-221-230. (In Russ)]
  9. Shan WL, Ma XL. How to establish acute myeloid leukemia xenograft models using immunodeficient mice. Asian Pacif J Cancer Prev. 2013;14(12):7057–63. doi: 10.7314/apjcp.2013.14.12.7057.
  10. Mambet C, Chivu-Economescu M, Matei L, et al. Murine models based on acute myeloid leukemia-initiating stem cells xenografting. World J Stem Cells. 2018;10(6):57–65. doi: 10.4252/wjsc.v10.i6.57.
  11. Wunderlich M, Mizukawa B, Chou FS, et al. AML cells are differentially sensitive to chemotherapy treatment in a human xenograft model. Blood. 2013;121(12):e90–e97. doi: 10.1182/blood-2012-10-464677.
  12. Saland E, Boutzen H, Castellano R, et al. A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia. Blood Cancer J. 2015;5(3):e297. doi: 10.1038/bcj.2015.19.
  13. Her Z, Yong KSM, Paramasivam K, et al. An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia. J Hematol Oncol. 2017;10(1):162. doi: 10.1186/s13045-017-0532-x.
  14. Johanna I, Straetemans T, Heijhuurs S, et al. Evaluating in vivo efficacy – toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells. J Immunother Cancer. 2019;7(1):69. doi: 10.1186/s40425-019-0558-4.
  15. Ruzicka M, Koenig LM, Formisano S, et al. RIG-I-based immunotherapy enhances survival in preclinical AML models and sensitizes AML cells to checkpoint blockade. Leukemia. 2020;34(4):1017–26. doi: 10.1038/s41375-019-0639-x.
  16. Wunderlich M, Chou F-S, Link KA, et al. AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3. Leukemia. 2010;24(10):1785–8. doi: 10.1038/leu.2010.158.
  17. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol. 2012;12(11):786–98. doi: 10.1038/nri3311.
  18. Theocharides AP, Rongvaux A, Fritsch K, et al. Humanized hemato-lymphoid system mice. Haematologica. 2016;101(1):5–19. doi: 10.3324/haematol.2014.115212.
  19. Nara N, Miyamoto T. Direct and serial transplantation of human acute myeloid leukaemia into nude mice. Br J Cancer. 1982;45(5):778–82. doi: 10.1038/bjc.1982.120.
  20. Okada S, Vaeteewoottacharn K, Kariya R. Application of Highly Immunocompromised Mice for the Establishment of Patient-Derived Xenograft (PDX) Models. Cells. 2019;8(8):889. doi: 10.3390/cells8080889.
  21. Sanchez PV, Perry RL, Sarry JE, et al. A robust xenotransplantation model for acute myeloid leukemia. Leukemia. 2009;23(11):2109–17. doi: 10.1038/leu.2009.143.
  22. Krevvata M, Shan X, Zhou C, et al. Cytokines increase engraftment of human acute myeloid leukemia cells in immunocompromised mice but not engraftment of human myelodysplastic syndrome cells. 2018;103(6):959–71. doi: 10.3324/haematol.2017.183202.
  23. Billerbeck E, Barry WT, Mu K, et al. Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rγ(null) humanized mice. Blood. 2011;117(11):3076–86. doi: 10.1182/blood-2010-08-301507.
  24. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. 2017;129(4):424–47. doi: 10.1182/blood-2016-08-733196.
  25. Osman J, Murad AM, Chin SF, et al. Highly Sensitive and Reliable Human Sex Determination Using Multiplex PCR. Asia Pacif J Mol Med. 2014;4:1–4.
  26. Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7(2):118–30. doi: 10.1038/nri2017.
  27. Voin V, Khalid S, Shrager S, et al. Neuroleukemiosis: Two Case Reports. Cureus. 2017;9(7):e1529. doi: 10.7759/cureus.1529.
  28. Almosailleakh M, Schwaller J. Murine Models of Acute Myeloid Leukaemia. Int J Mol Sci. 2019;20(2):453. doi: 10.3390/ijms20020453.
  29. Agliano A, Martin-Padura I, Mancuso P, et al. Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rgamma null mice generate a faster and more efficient disease compared to other NOD/scid-related strains. Int J Cancer. 2008;123(9):2222–7. doi: 10.1002/ijc.23772.
  30. Terpstra W, Prins A, Visser T, et al. Conditions for engraftment of human acute myeloid leukemia (AML) in SCID mice. 1995;9(9):1573–7.
  31. Lumkul R, Gorin N, Malehorn M, et al. Human AML cells in NOD/SCID mice: engraftment potential and gene expression. 2002;16(9):1818–26. doi: 10.1038/sj.leu.2402632.
  32. Martin-Padura I, Agliano A, Marighetti P, et al. Sex-related efficiency in NSG mouse engraftment. Blood. 2010;116(14):2616–7. doi: 10.1182/blood-2010-07-295584.
  33. Woiterski J, Ebinger M, Witte KE, et al. Engraftment of low numbers of pediatric acute lymphoid and myeloid leukemias into NOD/SCID/IL2Rcγnull mice reflects individual leukemogenecity and highly correlates with clinical outcome. Int J Cancer. 2013;133(7):1547–56. doi: 10.1002/ijc.28170.
  34. Ailles LE, Gerhard B, Kawagoe H, Hogge DE. Growth characteristics of acute myelogenous leukemia progenitors that initiate malignant hematopoiesis in nonobese diabetic/severe combined immunodeficient mice. Blood. 1999;94(5):1761–72. doi: 10.1182/blood.V94.5.1761.
  35. Pearce DJ, Taussig D, Zibara K, et al. AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML. 2006;107(3):1166–73. doi: 10.1182/blood-2005-06-2325.
  36. Monaco G, Konopleva M, Munsell M, et al. Engraftment of acute myeloid leukemia in NOD/SCID mice is independent of CXCR4 and predicts poor patient survival. Stem Cells. 2004;22(2):188–201. doi: 10.1634/stemcells.22-2-188.
  37. Rombouts WJ, Martens AC, Ploemacher RE. Identification of variables determining the engraftment potential of human acute myeloid leukemia in the immunodeficient NOD/SCID human chimera model. Leukemia. 2000;14(5):889–97. doi: 10.1038/sj.leu.2401777.
  38. Culen M, Kosarova Z, Jeziskova I, et al. The influence of mutational status and biological characteristics of acute myeloid leukemia on xenotransplantation outcomes in NOD SCID gamma mice. J Cancer Res Clin Oncol. 2018;144(7):1239–51. doi: 10.1007/s00432-018-2652-2.

Antibiotic Treatment of Febrile Neutropenia in Patients with Acute Leukemia

VA Okhmat, GA Klyasova, EN Parovichnikova, VV Troitskaya, EO Gribanova, VG Savchenko

National Medical Hematology Research Center, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Vladimir Aleksandrovich Okhmat, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)614-92-72; e-mail: okhmatvladimir@mail.ru

For citation: Okhmat VA, Klyasova GA, Parovichnikova EN, et al. Antibiotic Treatment of Febrile Neutropenia in Patients with Acute Leukemia. Clinical oncohematology. 2018;11(1):100-9.

DOI: 10.21320/2500-2139-2018-11-1-100-109


ABSTRACT

Aim. To estimate the efficacy of antibiotic treatment of febrile neutropenia in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

Materials & Methods. The prospective study (2013 to 2015) included 66 AML and 44 ALL patients receiving 480 chemotherapy cycles within the period of 6 months.

Results. Febrile neutropenia was registered during 242 (50 %) chemotherapy cycles occurring more frequently in AML than in ALL patients (93 % vs. 18 %, p < 0.0001). In AML patients infections were more common during induction and consolidation (98 and 89 %) phases compared to ALL patients who most commonly had infection during induction phase (55 %). Compared to ALL patients, AML patients had lower recovery rates after first-line antibiotic monotherapy (24 % vs. 57 %, < 0.0001), compared to combination therapy (37 % vs. 18 %, = 0.01). The use of beta-lactam antibiotics in ALL patients was associated with lower recovery rates during the induction phase compared to consolidation phase (47 % vs. 72 %, = 0.0004). In cases of granulocytopaenia longer that 14 days the clinical recovery rate with administration of the first-line antibiotics and carbapenems accounted for 23–24 % compared to 47 % with other antimicrobials, more commonly with antifungal (21 %) administration. In patients with fever of unknown origin the monotherapy with first-line antibiotics proved to be successful (45 %). In patients with clinically and microbiologically defined infections the best results were achieved by the combined treatment with the beta-lactam antibiotics and other drugs (43 %).

Conclusion. Antibiotic escalation has proved to be the optimal strategy in treatment of ALL patients and in cases of fever of unknown origin. The efficacy of the beta-lactam antibiotic monotherapy was lower in AML patients during the induction phase as well as in cases of continuous neutropenia (> 14 days) and clinically and microbiologically diagnosed infections. The adding of other antimicrobial administration resulted in the recovery in 37–48 % of cases.

Keywords: acute leukemia, AML, ALL, febrile neutropenia, fever of unknown origin, clinically and microbiologically defined infections, antibiotics.

Received: July 2, 2017

Accepted: October 20, 2017

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REFERENCES

  1. Паровичникова Е.Н., Троицкая В.В., Клясова Г.А. и др. Лечение больных острыми миелоидными лейкозами по протоколу российского многоцентрового рандомизированного исследования ОМЛ-01.10: результаты координационного центра. Терапевтический архив. 2014;86(7):14–23. [Parovichnikova EN, Troitskaya VV, Klyasova GA, et al. Treating patients with acute myeloid leukemias (AML) according to the protocol of the AML-01.10 Russian multicenter randomized trial: The coordinating center’s results. Terapevticheskii arkhiv. 2014;86(7):14–23. (In Russ)]
  2. Паровичникова Е.Н., Клясова Г.А., Исаев В.Г. и др. Первые итоги терапии Ph-негативных острых лимфобластных лейкозов взрослых по протоколу Научно-исследовательской группы гематологических центров России ОЛЛ-2009. Терапевтический архив. 2011;83(7):11–7. [Parovichnikova EN, Klyasova GA, Isaev VG, et al. Pilot results of therapy of adult Ph-negative acute lymphoblastic leukemia according to the protocol of Research Group of Russian Hematological Centers ALL-2009. Terapevticheskii arkhiv. 2011;83(7):11–7. (In Russ)]
  3. Войцеховский В.В., Груздова А.В., Филатова Е.А. и др. Анализ инфекционных осложнений гемобластозов в Амурской области.Бюллетень физиологии и патологии дыхания. 2012;46:64–8. [Voitsekhovskii VV, Gruzdova AV, Filatova EA, et al. The analysis of infectious complications of hemoblastosis in the Amur region. Byulleten’ fiziologii i patologii dykhaniya. 2012;46:64–8. (In Russ)]
  4. Mikulska M, Viscoli C, Orasch C, et al. Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J Infect. 2013;68(4):321–31. doi: 10.1016/j.jinf.2013.12.006.
  5. Клясова Г.А. Антимикробная терапия. В кн.: Программное лечение заболеваний системы крови: сборник алгоритмов диагностики и протоколов лечения заболеваний системы крови. Под ред. В.Г. Савченко. М.: Практика, 2012. С. 827–54. [Klyasova GA. Antimicrobial therapy. In: Savchenko VG, ed. Programmnoe lechenie zabolevanii sistemy krovi: sbornik algoritmov diagnostiki i protokolov lecheniya zabolevanii sistemy krovi. (Program treatment of blood system diseases.) Moscow: Praktika Publ.; 2012. pp. 829–53. (In Russ)]
  6. Averbuch D, Cordonnier C, Livermore DM, et al. Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: Guidelines of the 4th European conference on Infections in Leukemia (ECIL-4, 2011). Haematologica. 2013;98(12):1836–47. doi: 10.3324/haematol.2013.091330.
  7. Tumbarello M, Sanguinetti M, Montuori E, et al. Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment. Antimicrob Agents Chemother. 2007;51(6):1987–94. doi:10.1128/AAC.01509–06.
  8. Савченко В.Г., Паровичникова Е.Н., Афанасьев Б.В. и др. Национальные клинические рекомендации по диагностике и лечению острых миелоидных лейкозов взрослых. Гематология и трансфузиология. 2014;59(S2):2–29. [Savchenko VG, Parovichnikova EN, Afanas’ev BV, et al. National clinical guidelines for the diagnosis and treatment of acute myeloid leukemia in adults. Gematologiya i transfusiologiya. 2014;59(S2):2–29. (In Russ)]
  9. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649–55.
  10. Averbuch D, Orasch C, Cordonnier C, et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica. 2013;98(12):1826–35. doi: 10.3324/haematol.2013.091025.
  11. Клясова Г.А., Коробова А.Г., Фролова И.Н. и др. Детекция энтеробактерий с продукцией β-лактамаз расширенного спектра у больных острыми миелоидными лейкозами и лимфомами при поступлении в стационар. Гематология и трансфузиология. 2016;61(1):25–32. doi: 10.18821/0234-5730-2016-61-1-25-32. [Klyasova GA, Korobova AG, Frolova IN, et al. Detection of extended-spectrum β-lactamase producing Enterobacteriaceae (ESBL-E) among patients with acute myeloid leukemia and lymphoma upon admission to hospital. Gematologiya i transfusiologiya. 2016;61(1):25–32. doi: 10.18821/0234-5730-2016-61-1-25-32. (In Russ)]
  12. Охмат В.А., Клясова Г.А., Коробова А.Г. и др. Следует ли назначать карбапенемы всем больным с фебрильной нейтропенией и колонизацией энтеробактериями с продукцией β-лактамаз расширенного спектра? Онкогематология. 2016;11(3):49–57. doi: 10.17650/1818-8346-2016-11-3-49-57. [Okhmat VA, Klyasova GA, Korobova AG. Should to all patients with febrile neutropenia and colonization with extended-spectrum β-lactamase-producing Enterobacteriaceae carbapenems be appointed? Oncohematology. 2016;11(3):49–57. doi: 10.17650/1818-8346-2016-11-3-49-57. (In Russ)]
  13. Aynioglu Mujeeb VR, Jambunathan P, Tyagi A. Comparison of Efficacy of Piperacillin/Tazobactam Vs Cefoperazone/Sulbactam as Empirical Therapy in Patients with Febrile Neutropenia. Ann Int Med Dent Res. 2017;3(2):51–5. doi: 10.21276/aimdr.2017.3.2.me12.
  14. Demir HA, Kutluk T, Ceyhan M, et al. Comparison of sulbactam-cefoperazone with carbapenems as empirical monotherapy for febrile neutropenic children with lymphoma and solid tumors. Pediatr Hematol Oncol. 2011;28(4):299–310. doi: 3109/08880018.2011.552937.
  15. Jing Y, Li J, Yuan L, et al. Piperacillin‐tazobactam vs. imipenem‐cilastatin as empirical therapy in hematopoietic stem cell transplantation recipients with febrile neutropenia. Clin Transplant. 2016;30(3):263–9. doi: 1111/ctr.12685.
  16. Охмат В.А., Клясова Г.А., Паровичникова Е.Н. и др. Спектр и этиология инфекционных осложнений у больных острыми миелоидными лейкозами на этапах индукции и консолидации ремиссии. Гематология и трансфузиология. 2017;62(1):9–15. [Okhmat VA, Klyasova GA, Parovichnikova EN, et al. Spectrum and epidemiology of infection complications in patients with acute myeloid leukemia during induction and consolidation chemotherapy. Gematologiya i transfusiologiya. 2017;62(1):9–15. (In Russ)]
  17. Pizzo PA. After empiric therapy: what to do until the granulocyte comes back. Rev Infect Dis. 1987;9(1):214–9. doi: 1093/clinids/9.1.214.
  18. Link H, Maschmeyer G, Meyer PF, et al. Interventional antimicrobial therapy in febrile neutropenic patients. Ann Hematol. 1994;69(5):231–43. doi: 1007/BF01700277.
  19. Viscoli C, Cometta A, Kern WV, et al. Piperacillin-tazobactam monotherapy in high-risk febrile and neutropenic cancer patients. Clin Microbiol Infect. 2006;12(3):212–6. doi: 10.1111/j.1469-0691.2005.01297.x.

Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia

LL Girshova, IG Budaeva, EG Ovsyannikova, SO Kuzin, DV Motorin, RSh Badaev, DB Zammoeva, VV Ivanov, KV Bogdanov, OS Pisotskaya, YuV Mirolyubova, TS Nikulina, YuA Alekseeva, AYu Zaritskii

VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Irina Garmaevna Budaeva, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(931)351-07-06; e-mail: irina2005179@mail.ru

For citation: Girshova LL, Budaeva IG, Ovsyannikova EG, et al. Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia. Clinical oncohematology. 2017;10(4):485–93 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-485-493


ABSTRACT

Background. Acute myeloblastic leukemia (AML) with NPM1 mutation amounts to 30 % of all AML and is characterized by good prognosis with the exception of cases with FLT3-ITD mutation. Despite the good prognosis, the likelihood of relapses in patients with NPM1 mutation may significantly differ. Thus, the estimation of the minimal residual disease (MRD) after chemotherapy and during follow-up is becoming increasingly important. This approach will make it possible to predict the sensitivity of a tumoral clone to chemotherapy.

Aim. To evaluate the prognostic value of highly specific marker (NPM1 mutation) and non-specific marker (WT1 overexpression) of MRD, as well as to identify the correlation between the levels of NPM1 and WT1 at different stages of therapy and in the follow-up period.

Materials & Methods. The research included 14 patients with AML. All patients had the NPM1 mutation and WT1 overexpression: 50 % of patients had additional molecular markers (BAALC overexpression, FLT3-ITD, DNMT3A, and MLL mutations). Real-time PCR was used for long-term monitoring of WT1 expression levels and NPM1 mutation.

Results. The median decrease of NPM1 levels after the induction therapy was 3 log. All patients had relapses, NPM1 mutation, and lower rates of OS/RFS, which significantly correlated with prognostically negative molecular markers. There were no statistically significant differences in RFS in groups with the decrease of WT1 expression level < 2 log and > 2 log on day 28 of treatment. At the same time, the decrease of WT1 expression by > 2 log was associated with significant differences in early relapses, which correlated with the decrease of NPM1 levels (> and < than 3 log) is revealed. RFS rates were higher in patients with WT1 expression level of < 100 per 104 copies ABL on day 28 and WT1 of < 250 per 104 copies ABL on day 14 of treatment. WT1 expression was significantly lower on days 14 and 28 in patients with NPM1 decrease of > 3 log on day 28. The decrease in WT1 expression of < 100 per 104 copies ABL on day 28 was more common in patients with isolated NPM1 mutation, compared to patients with additional negative molecular markers.

Conclusion. The decrease in NPM1 levels after the induction therapy may serve as reliable prognostic marker of RFS and OS rates. New correlation between the degree of NPM1 reduction and the presence of additional molecular markers was established. Highly specific (NPM1 mutation) was shown to be more specific compared to non-specific markers (WT1 overexpression). The research showed the predictive value of a lower limit level of WT1 on day 28 of treatment (100 per 104 copies ABL), and for the first time, the importance of the early assessment WT1 expression reduction on day 14 of induction therapy.

Keywords: acute myeloblastic leukemia, AML, NPM1, WT1, molecular monitoring.

Received: February 22, 2017

Accepted: May 26, 2017

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REFERENCES

  1. Dohner H, Estey E, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–74. doi: 10.1182/blood-2009-07-235358.
  2. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47.  doi: 10.1182/blood-2016-08-733196.
  3. Yin C.C. Detection and molecular monitoring of Minimal residual diseases in acute myeloid leukemias. J Mol Biomark Diagn. 2012;3(2):1000e105–6. doi: 10.4172/2155-9929.1000e106.
  4. Hourigan CS, Karp JE. Minimal residual disease in acute myeloid leukaemia. Nat Rev Clin Oncol. 2013;10(8):460–71. doi: 10.1038/nrclinonc.2013.100.
  5. Gabert J, Beillard E, van der Velden VH, et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia–a Europe Against Cancer program. Leukemia. 2003;17(12):2318–57. doi: 10.1038/sj.leu.2403135.
  6. Cilloni D, Gottardi E, de Micheli D, et al. Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia. 2002;16(10):2115–21. doi: 10.1038/sj.leu.2402675.
  7. Cilloni D, Saglio G. Usefulness of quantitative assessment of Wilms tumor suppressor gene expression in chronic myeloid leukemia patients undergoing imatinib therapy. Semin Hematol. 2003;40:37–41. doi: 10.1053/shem.2003.50040.
  8. Ogawa H, Tamaki H, Ikegame K, et al. The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogenic stem cell transplantation in acute type leukemia. Blood. 2003;101(5):1698–702. doi: 10.1182/blood-2002-06-1831.
  9. Cilloni D, Messa F, Rosso V, et al. Increase sensitivity to chemotherapeutical agents and cytoplasmatic interaction between NPM leukemic mutant and NF-kappaB in AML carrying NPM1 mutations. Leukemia. 2008;22(6):1234–40. doi: 10.1038/leu.2008.68.
  10. Cilloni D, Renneville A, Hermitte F, et al. Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: A European LeukemiaNet study. J Clin Oncol. 2009;27(31):5195–201. doi: 10.1200/jco.2009.22.4865.
  11. Pozzi S, Geroldi S, Tedone E, et al. Leukemia relapse after allogeneic transplants for acute myeloid leukaemia: predictive role of WT1 expression. Br J Haematol. 2013;160(4):503–9. doi: 10.1111/bjh.12181.
  12. Grazia CD, Pozzi S, Geroldi S, et al. Wilms Tumor 1 Expression and Pre-Emptive Immunotherapy in Patients with Acute Myeloid Leukemia Undergoing an Allogeneic Hemopoietic Stem Cell Transplant. Biol Blood Marrow Transplant. 2016;22(7):1242–6. doi: 10.1016/j.bbmt.2016.03.005.
  13. Nomdederu J, Hoyos M, Carricondo M, et al. Bone marrow WT1 levels at diagnosis, post-induction and post-intensification in adult de novo AML. Leukemia. 2013;27(11):2157–64. doi: 10.1038/leu.2013.111.
  14. Schnittger S, Kern W, Tschulik C, et al. Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood. 2009;114(11):2220–31. doi: 10.1182/blood-2009-03-213389.
  15. Falini B, Nicoletti I, Martelli M, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood. 2007;109(3):874–85. doi: 10.1182/blood-2006-07-012252.
  16. Chang JH, Olson MO. Structure of the gene for rat nucleolar protein B23. J Biol Chem. 1990;265(30):18227–33.
  17. Wang W, Budhu A, Forgues M, et al. Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication. Nat Cell Biol. 2005;7(8):823–30. doi: 10.1038/ncb1282.
  18. Ghandforoush NA, Chahardouli B, Rostami S,et. al. Evaluation of Minimal Residual Disease in Acute Myeloid Leukemia with NPM1 Marker. Int J Hematol Oncol Stem Cell Res. 2016;10(3):147–52.
  19. Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254–66. doi: 10.1056/NEJMoa041974.
  20. Nafea D, Rahman MA, Boris D, et al. Incidence and prognostic value of NPM1 and FLT3 gene mutations in AML with normal karyotype. Open Hematol J. 2011;5(1):14–20. doi: 10.2174/1874276901105010014.
  21. Schneider F, Hoster E, Unterhalt M, et al. NPM1 but not FLT3-ITD mutations predict early blast cell clearance and CR rate in patients with normal karyotype AML (NK-AML) or high-risk myelodysplastic syndrome (MDS). Blood. 2009;113(21):5250–3. doi: 10.1182/blood-2008-09-172668.
  22. Dohner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106(12):3740–6. doi: 10.1182/blood-2005-05-2164.
  23. Schnittger S, Schoch C, Kern Q. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106(12):3733–9. doi: 10.1182/blood-2005-06-2248.
  24. Kronke J, Schlenk RF, Jensen KO, et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a Study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol. 2011;29(19):2709–16. doi: 10.1200/JCO.2011.35.0371.
  25. Gorin N-C, Labopin M, Meloni G, et al. Impact of FLT3 ITD/NPM1 mutation status in adult patients with acute myelocytic leukemia autografted in first remission. Haematologica. 2013;98(2):e12–4. doi: 10.3324/haematol.2012.064436.
  26. Patel JL, Schumacher JA, Frizzell K, et al. Coexisting and cooperating mutations in NPM1-mutated acute myeloid leukemia. Leukemia Research 2017;56:7–12. doi: 10.1016/j.leukres.2017.01.027.
  27. Yoon J, Kim H, Shin S, et al. Implication of higher BAALC expression in combination with other gene mutations in adult cytogenetically normal AML. Leuk Lymphoma. 2013;55(1):110–20. doi: 10.3109/10428194.2013.800869.
  28. Tiribellia M, Raspadorib D, Geromin A, et al. High CD200 expression is associated with poor prognosis in cytogenetically normal acute myeloid leukemia, even in FlT3-ITD/NPM1+ patients. Leuk Res. 2017;58:31–8. doi: 10.1016/j.leukres.2017.04.001.
  29. Damiani D, Tiribelli M, Raspadori D, et al. Clinical impact of CD200 expression in patients with acute myeloid leukemia and correlation with other molecular prognostic factors. Oncotarget. 2015;6(30):30212–21. doi: 10.18632/oncotarget.4901.
  30. Hubmann M, Kohnke T, Hoster E, et al. Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse. Haematologica. 2014;99(8):1317–25. doi: 10.3324/haematol.2014.104133.
  31. Dohner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106(12):3740–6. doi: 10.1182/blood-2005-05-2164.
  32. Rollig C, Bornhаuser M, Kramer M, et al. Allogeneic Stem-Cell Transplantation in Patients with NPM1-Mutated Acute Myeloid Leukemia: Results from a Prospective Donor Versus No-Donor Analysis of Patients After Upfront HLA Typing Within the SAL-AML 2003 Trial. J Clin Oncol. 2015;33(5):403–10. doi: 10.1200/JCO.2013.54.4973.
  33. Balsat M, Renneville A, Thomas X, et al. Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia With NPM1 Mutation: A Study by the Acute Leukemia French Association Group. J Clin Oncol. 2016;35(2):185–93. doi: 10.1200/JCO.2016.67.1875.
  34. Kristensen T, Mоller MB, Friis L, et al. NPM1 mutation is a stable marker for minimal residual disease monitoring in acute myeloid leukaemia patients with increased sensitivity compared to WT1 expression. Eur J Haematol. 2011;87(5):400–8. doi: 10.1111/j.1600-0609.2011.01673.х.
  35. Barragan E, Pajuelo JC, Ballester S, et al. Minimal residual disease detection in acute myeloid leukemia by mutant nucleophosmin (NPM1): comparison with WT1 gene expression. Clin Chim Acta. 2008;395(1–2):120–3. doi: 10.1016/j.cca.2008.05.021.
  36. Gorello P, Cazzaniga G, Alberti F, et al. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia. 2006;20(6):1103–8. doi: 10.1038/sj.leu.2404149.
  37. Paietta E. Minimal residual disease in acute myeloid leukemia: coming of age. Hematology Am Soc Hematol Educ Program. 2012;1:35–42. doi: 10.1182/asheducation-2012.1.35.
  38. Verhaak RGW, Goudswaard CS, van Putten W, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106(12):3747–54. doi: 10.1182/blood-2005-05-2168.
  39. Dvorakova D, Racil Z, Jeziskova I, et al. Monitoring of minimal residual disease in acute myeloid leukemia with frequent and rare patient-specific NPM1 mutations. Am J Hematol. 2010;85(12):926–9. doi: 10.1002/ajh.21879.
  40. Chou WC, Tang JL, Wu SJ, et al. Clinical implications of minimal residual disease monitoring by quantitative polymerase chain reaction in acute myeloid leukemia patients bearing nucleophosmin (NPM1) mutations. Leukemia. 2007;21(5):998–1004. doi: 10.1038/sj.leu.2404637.
  41. Meloni G, Mancini M, Gianfelici V, et al. Late relapse of acute myeloid leukemia with mutated NPM1 after eight years: evidence of NPM1 mutation stability. Haematologica. 2009;94(2):298–300. doi: 10.3324/haematol.2008.000059.
  42. Papadaki C, Dufour A, Seibl M, et al. Monitoring minimal residual disease in acute myeloid leukaemia with NPM1 mutations by quantitative PCR: clonal evolution is a limiting factor. Br J Haematol. 2009;144(4):517–23. doi: 10.1111/j.1365-2141.2008.07488.х.
  43. Kayser S, Walter RB, Stock W, Schlenk RF. Minimal residual disease in acute myeloid leukemia-current status and future perspectives. Curr Hematol Malig Rep. 2015;10(2):132–44. doi: 10.1007/s11899-015-0260-7.
  44. Terre C, Rousselot P, Dombret H, et al. MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin. Oncotarget. 2014;5(15):6280–8. doi: 10.18632/oncotarget.2196.
  45. Ommen HB, Schnittger S, Jovanovic JV, et al. Strikingly different molecular relapse kinetics in NPM1c, PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias. Blood. 2010;115(2):198–205. doi: 10.1182/blood-2009-04-212530.
  46. Гиршова Л.Л., Овсянникова Е.Г., Кузин С.О. и др. Молекулярный мониторинг уровня транскрипта RUNX1-RUNX1T1 при острых миелобластных лейкозах на фоне терапии. Клиническая онкогематология. 2016;9(4):456–64. doi: 10.21320/2500-2139-2016-9-4-456-464.[Girshova LL, Ovsyannikova EG, Kuzin SO, et al. Molecular Monitoring of RUNX1-RUNX1T1 Transcript Level in Acute Myeloblastic Leukemias on Treatment. Clinical oncohematology. 2016;9(4):456–64. doi: 10.21320/2500-2139-2016-9-4-456-464. (In Russ)]
  47. Balsat M, Renneville A, Thomas X, et al. Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia With NPM1 Mutation: A Study by the Acute Leukemia French Association Group. J Clin Oncol. 2016;35(2):185–93. doi: 10.1200/JCO.2016.67.1875.
  48. Rossi G, et al. Comparison between multiparameter flow cytometry and WT1-RNA quantification in monitoring minimal residual disease in acute myeloid leukemia without specific molecular targets. Leuk Res. 2012;36(4):401–6. doi: 10.1016/j.leukres.2011.11.020.

Cytogenetic and Molecular Genetic Prognostic Factors of Acute Myeloid Leukemia

AV Misyurin

NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Andrei Vital’evich Misyurin, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: and@genetechnology.ru

For citation: Misyurin AV. Cytogenetic and Molecular Genetic Prognostic Factors of Acute Myeloid Leukemia. Clinical oncohematology. 2017;10(2):227–34 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-227-234


ABSTRACT

The review presents data on the diagnostic and prognostic value of cytogenetic and molecular genetic markers of acute myeloid leukemia (AML). It demonstrates that some cases, different types of AML subdivided on the basis of clinical and morphological characteristics earlier may be distinguished based on identification of specific genetic and chromosomal defects. However, some repeated chromosomal abnormalities may be detected in AML patients that may be assigned to different variants based in clinical and morphocytochemical signs. At present, it is widely accepted that changes in the karyotype are the key prognostic factors which are more important than criteria based on morphological and cytochemical signs. Therefore, the risk-adaptive therapy of AML should be chosen based on the cytogenetic test findings. The review contains a section discussing gene mutations known to date that may affect the AML treatment outcome.

Keywords: AML, chromosomal aberration, chimeric oncogene, gene expression, gene mutation.

Received: September 16, 2016

Accepted: January 3, 2017

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REFERENCES

  1. Гематология: национальное руководство. Под ред. О.А. Рукавицына. М.: ГЭОТАР-Медиа, 2015. 776 с.
    [Rukavitsyn OA, ed. Gematologiya: natsional’noe rukovodstvo. (Hematology: national guidelines.) Moscow: GEOTAR-Media Publ.; 2015. 776 p. (In Russ)]
  2. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008.
  3. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937–51. doi: 10.1182/blood-2009-03-209262.
  4. Zerbini MCN, Soares FA, Velloso EDRP, et al. World Health Organization classification of tumors of hematopoietic and lymphoid tissues, 2008: major changes from the 3rd edition. Revista da Associacao Medica Brasileira. 2011;57(1): 6–73. doi: 10.1590/S0104-42302011000100019.
  5. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976;33(4):451–8. doi: 10.1111/j.1365-2141.1976.tb03563.
  6. Kuhnl A, Grimwade D. Molecular markers in acute myeloid leukaemia. Int J Hematol. 2012;96(2):153–63. doi: 10.1007/s12185-012-1123-9.
  7. Burnett AK, Wheatley K, Goldstone AH, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol. 2002;118(2):385–400. doi: 10.1046/j.1365-2141.2002.03724.x.
  8. Cornelissen JJ, van Putten WL, Verdonck LF, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood. 2007;109(9):3658–66. doi: 10.1182/blood-2006-06-025627.
  9. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96(13):4075–83.
  10. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116(3):354–65. doi: 10.1182/blood-2009-11-254441.
  11. Blum W, Mrozek K, Ruppert AS, et al. Adult de novo acute myeloid leukemia with t(6;11)(q27;q23): results from Cancer and Leukemia Group B Study 8461 and review of the literature. Cancer. 2005;103(6):1316. doi: 10.1002/cncr.20931
  12. Krauter J, Wagner K, Schafer I, et al. Prognostic factors in adult patients up to 60 years old with acute myeloid leukemia and translocations of chromosome band 11q23: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2009;27(18):3000–6. doi: 10.1200/jco.2008.16.7981.
  13. von Neuhoff C, Reinhardt D, Sander A, et al. Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. J Clin Oncol. 2010;28(16):2682–9. doi: 10.1200/JCO.2009.25.6321.
  14. Rucker FG, Bullinger L, Schwaenen C, et al. Disclosure of candidate genes in acute myeloid leukemia with complex karyotypes using microarray-based molecular characterization. J Clin Oncol. 2006;24(24):3887–94. doi: 10.1200/jco.2005.04.5450.
  15. Mrozek K. Cytogenetic, molecular genetic, and clinical characteristics of acute myeloid leukemia with a complex karyotype. Semin Oncol. 2008;35(4):365–77. doi: 10.1053/j.seminoncol.2008.04.007.
  16. Breems DA, Van Putten WL, De Greef GE, et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 2008;26(29):4791–7. doi: 10.1200/JCO.2008.16.0259.
  17. Smith ML, Hills RK, Grimwade D. Independent prognostic variables in acute myeloid leukaemia. Blood Rev. 2011;25(1):39–51. doi: 10.1016/j.blre.2010.10.002.
  18. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289–301. doi: 10.1056/NEJMoa0810069.
  19. Metzeler KH, Maharry K, Radmacher MD, et al. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2011;29(10):1373–81. doi: 10.1200/JCO.2010.32.7742.
  20. Chou WC, Chou SC, Liu CY, et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood. 2011;118(14):3803–10. doi: 10.1182/blood-2011-02-339747.
  21. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–66.
  22. Thol F, Damm F, Wagner K, et al. Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood. 2010(4);116:614–6. doi: 10.1182/blood-2010-03-272146.
  23. Chou WC, Hou HA, Chen CY, et al. Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation. Blood. 2010;115(14):2749–54. doi: 10.1182/blood-2009-11-253070.
  24. Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2010;28(14):2348–55. doi: 10.1200/jco.2009.27.3730.
  25. Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28(22):3636–43. doi: 10.1200/jco.2010.28.3762.
  26. Schnittger S, Haferlach C, Ulke M, et al. IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood. 2010;116(25):5486–96. doi: 10.1182/blood-2010-02-267955.
  27. Ravandi F, Patel K, Luthra R, et al. Prognostic significance of alterations in IDH enzyme isoforms in patients with AML treated with high-dose cytarabine and idarubicin. Cancer. 2012;118(10):2665–73. doi: 10.1002/cncr.26580.
  28. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424–33. doi: 10.1056/NEJMoa1005143.
  29. Thol F, Damm F, Ludeking A, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011;29:2889–96. doi: 10.1200/JCO.2011.35.4894.
  30. Shen Y, Zhu YM, Fan X, et al. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood. 2011;118(20):5593–603. doi: 10.1182/blood-2011-03-343988.
  31. Hou HA, Kuo YY, Liu CY, et al. DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications. Blood. 2011(2);119:559–68. doi: 10.1182/blood-2011-07-369934.
  32. Renneville A, Boissel N, Nibourel O, et al. Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association. Leukemia. 2012;26(6):1247–54. doi: 10.1038/leu.2011.382.
  33. Marcucci G, Metzeler KH, Schwind S, et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2012;30(7):742–50. doi: 10.1200/jco.2011.39.2092.
  34. Markova J, Michkova P, Burckova K, et al. Prognostic impact of DNMT3A mutations in patients with intermediate cytogenetic risk profile acute myeloid leukemia. Eur J Haematol. 2012;88(2):128–35. doi: 10.1111/j.1600-0609.2011.01716.x.
  35. King-Underwood L, Renshaw J, Pritchard-Jones K. Mutations in the Wilms’ tumor gene WT1 in leukemias. Blood. 1996;87(6):2171–9.
  36. Virappane P, Gale R, Hills R, et al. Mutation of the Wilms’ tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol. 2008;26(33):5429–35. doi: 10.1200/jco.2008.16.0333.
  37. Paschka P, Marcucci G, Ruppert AS, et al. Wilms’ tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol. 2008;26(28):4595–602. doi: 10.1200/JCO.2007.15.2058.
  38. Boissel N, Leroy H, Brethon B, et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia. 2006;20(6):965–70. doi: 10.1038/sj.leu.2404188.
  39. Paschka P, Marcucci G, Ruppert AS, et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006;24(24):3904–11. doi: 10.1200/JCO.2006.06.9500.
  40. Cairoli R, Beghini A, Grillo G, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood. 2006;107(9):3463–8. doi: 10.1182/blood-2005-09-3640.
  41. Schnittger S, Kohl TM, Haferlach T, et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood. 2006;107(5):1791–9. doi: 10.1182/blood-2005-04-1466.
  42. Gelsi-Boyer V, Trouplin V, Adelaide J, et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol. 2009;145(6):788–800. doi: 10.1111/j.1365-2141.2009.07697.x.
  43. Chou WC, Huang HH, Hou HA, et al. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood. 2010;116(20):4086–94. doi: 10.1182/blood-2010-05-283291.
  44. Metzeler KH, Becker H, Maharry K, et al. ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category. Blood. 2011;118(26):6920–9. doi: 10.1182/blood-2011-08-368225.
  45. Pratcorona M, Abbas S, Sanders MA, et al. Acquired mutations in ASXL1 in acute myeloid leukemia: prevalence and prognostic value. Haematologica. 2012;97(3):388–92. doi: 10.3324/haematol.2011.051532.
  46. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–89. doi: 10.1056/NEJMoa1112304.
  47. Grossmann V, Tiacci E, Holmes AB, et al. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood. 2011;118(23):6153–63. doi: 10.1182/blood-2011-07-365320.
  48. Li M, Collins R, Jiao Y, et al. Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia. Blood. 2011;118(22):5914–7. doi: 10.1182/blood-2011-05-356204.
  49. Van Vlierberghe P, Patel J, Abdel-Wahab O, et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia. 2011;25(1):130–4. doi: 10.1038/leu.2010.247.
  50. Mano H. Stratification of acute myeloid leukemia based on gene expression profiles. Int J Hematol. 2004;80(5):389–94. doi: 10.1532/ijh97.04111.
  51. Marcucci G, Mrozek K, Radmacher MD, et al. The prognostic and functional role of microRNAs in acute myeloid leukemia. Blood. 2011;117(4):1121–9. doi: 10.1182/blood-2010-09-191312.
  52. Smith ML, Hills RK, Grimwade D. Independent prognostic variables in acute myeloid leukaemia. Blood Rev. 2011;25(1):39–51. doi: 10.1016/j.blre.2010.10.002.
  53. Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254–66. doi: 10.1056/NEJMoa041974.
  54. Dohner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106(12):3740–6. doi: 10.1182/blood-2005-05-2164.
  55. Thiede C, Creutzig E, Illmer T, et al. Rapid and sensitive typing of NPM1 mutations using LNA-mediated PCR clamping. Leukemia. 2006;20(10):1897–9. doi: 10.1038/sj.leu.2404367.
  56. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909–18. doi: 10.1056/NEJMoa074306.
  57. Green CL, Koo KK, Hills RK, et al. Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol. 2010;28(16):2739–47. doi: 10.1200/JCO.2009.26.2501.
  58. Grisendi S, Mecucci C, Falini B, et al. Nucleophosmin and cancer. Nat Rev Cancer. 2006;6(7):493–505. doi: 10.1038/nrc1885.
  59. Freeman SD, Jovanovic JV, Grimwade D. Development of minimal residual disease-directed therapy in acute myeloid leukemia. Semin Oncol. 2008;35(4):388–400. doi: 10.1053/j.seminoncol.2008.04.009.
  60. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10(12):1911–8.
  61. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98(6):1752–9. doi: 10.1182/blood.V98.6.1752.
  62. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99(12):4326–35. doi: 10.1182/blood.V99.12.4326.
  63. Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19(8):1345–9. doi: 10.1038/sj.leu.2403838.
  64. Mead AJ, Linch DC, Hills RK, et al. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients. Blood. 2007;110(4):1262–70. doi: 10.1182/blood-2006-04-015826.
  65. Bacher U, Haferlach C, Kern W, et al. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters—an analysis of 3082 patients. Blood. 2008;111(5):2527–37. doi: 10.1182/blood-2007-05-091215.
  66. Whitman SP, Ruppert AS, Radmacher MD, et al. FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications. Blood. 2008;111(3):1552–9. doi: 10.1182/blood-2007-08-107946.
  67. Gale RE, Hills R, Pizzey AR, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood. 2005;106(12):3768–76. doi: 10.1182/blood-2005-04-1746.
  68. Souza Melo CP, Campos CB, Dutra AP, et al. Correlation between FLT3-ITD status and clinical, cellular and molecular profiles in promyelocytic acute leukemias. Leuk Res. 2015;39(2):131–7. doi: 10.1016/j.leukres.2014.11.010.
  69. Cicconi L, Divona M, Ciardi C, et al. PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy. Leukemia. 2016;30(10):1987–92. doi: 10.1038/leu.2016.122.
  70. Radomska HS, Huettner CS, Zhang P, et al. CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol. 1998;18(7):4301–14. doi: 10.1128/mcb.18.7.4301.
  71. Pabst T, Mueller BU, Zhang P, et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet. 2001;27(3):263–70. doi: 10.1038/85820.
  72. Smith ML, Cavenagh JD, Lister TA, et al. Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med. 2004;351(23):2403–7. doi: 10.1056/NEJMoa041331.
  73. Pabst T, Eyholzer M, Fos J, et al. Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. Br J Cancer. 2009;100(8):1343–6. doi: 10.1038/sj.bjc.6604977.
  74. Kirstetter P, Schuster MB, Bereshchenko O, et al. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. Cancer Cell. 2008;13(4):299–310. doi: 10.1016/j.ccr.2008.02.008.
  75. Wouters BJ, Lowenberg B, Erpelinck-Verschueren CA, et al. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood. 2009;113(13):3088–91. doi: 10.1182/blood-2008-09-179895.
  76. Taskesen E, Bullinger L, Corbacioglu A, et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood. 2011;117(8):2469–75. doi: 10.1182/blood-2010-09-307280.
  77. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–74. doi: 10.1182/blood-2009-07-235358.
  78. Ito S, Shen L, Dai Q, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333(6047):1300–3. doi: 10.1126/science.1210597.
  79. Abdel-Wahab O, Mullally A, Hedvat C, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009;114(1):144–7. doi: 10.1182/blood-2009-03-210039.
  80. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–67. doi: 10.1016/j.ccr.2010.11.015.
  81. Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468(7325):839–43. doi: 10.1038/nature09586.
  82. Langemeijer SM, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet. 2009;41(7):838–42. doi: 10.1038/ng.391.
  83. Jankowska AM, Szpurka H, Tiu RV, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood. 2009;113(25):6403–10. doi: 10.1182/blood-2009-02-205690.
  84. Gaidzik VI, Paschka P, Spath D, et al. TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML Study Group. J Clin Oncol. 2012;30(12):1350–7. doi: 10.1200/JCO.2011.39.2886.
  85. Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225–34. doi: 10.1016/j.ccr.2010.01.020.
  86. Gross S, Cairns RA, Minden MD, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207(2):339–44. doi: 10.1084/jem.20092506.
  87. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113(9):1875–91. doi: 10.1182/blood-2008-04-150250.
  88. Diehl F, Rossig L, Zeiher AM, et al. The histone methyltransferase MLL is an upstream regulator of endothelial-cell sprout formation. Blood. 2007;109(4):1472–8. doi: 10.1182/blood-2006-08-039651.
  89. Li Y, Han J, Zhang Y, et al. Structural basis for activity regulation of MLL family methyltransferases. Nature. 2016;530(7591):447–52. doi: 10.1038/nature16952.
  90. Bower M, Parry P, Carter M, et al. Prevalence and clinical correlations of MLL gene rearrangements in AML-M4/5. Blood. 1994;84(11):3776–80.
  91. Schichman SA, Caligiuri MA, Strout MP, et al. ALL-1 tandem duplication in acute myeloid leukemia with a normal karyotype involves homologous recombination between Alu elements. Cancer Res. 1994;54(16):4277–80.
  92. Caligiuri MA, Schichman SA, Strout MP, et al. Molecular rearrangement of the ALL-1 gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocations. Cancer Res. 1994;54(2):370–3.
  93. Park JP, Ladd SL, Ely P, et al. Amplification of the MLL region in acute myeloid leukemia. Cancer Genet Cytogenet. 2000;121(2):198–205. doi: 10.1016/S0165-4608(00)00256-9.
  94. Schnittger S, Kinkelin U, Schoch C, et al. Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. Leukemia. 2000;14(5):796–804. doi: 10.1038/sj.leu.2401773.
  95. Slovak ML, Traweek ST, Willman CL, et al. Trisomy 11: an association with stem/progenitor cell immunophenotype. Br J Haematol. 1995;90(2):266–73. doi: 10.1111/j.1365-2141.1995.tb05146.x.
  96. Strout MP, Marcucci G, Bloomfield CD, et al. The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia. Proc Natl Acad Sci USA. 1998;95(5):2390–5. doi: 10.1073/pnas.95.5.2390.
  97. Klymenko S, Bebeshko V, Bazyka D, et al. AML1 gene rearrangements and mutations in radiation-associated acute myeloid leukemia and myelodysplastic syndromes. J Rad Res. 2005;46(2):249–55. doi: 10.1269/jrr.46.249.
  98. Мисюрин В.А., Лукина А.Е., Мисюрин А.В. и др. Особенности соотношения уровней экспрессии генов PRAME и PML/RARA в дебюте острого промиелоцитарного лейкоза. Российский биотерапевтический журнал. 2014;13(1):9–16.
    [Misyurin VA, Lukina AE, Misyurin AV. A ratio between gene expression levels of PRAME and PML/RARA at the onset of acute promyelocytic leukemia and clinical features of the disease. Rossiiskii bioterapevticheskii zhurnal. 2014;13(1):9–16. (In Russ)]
  99. Мисюрин А.В. Основы молекулярной диагностики онкогематологических заболеваний. Российский биотерапевтический журнал. 2016;15(4):18–24. doi: 10.17650/1726-9784-2016-15-4-18-24.
    [Misyurin AV. Fundamentals of the molecular diagnosis of oncohematological diseases. Rossiiskii bioterapevticheskii zhurnal. 2016;15(4):18–24. doi: 10.17650/1726-9784-2016-15-4-18-24. (In Russ)]

 

 

Molecular Monitoring of RUNX1-RUNX1T1 Transcript Level in Acute Myeloblastic Leukemias on Treatment

LL Girshova, EG Ovsyannikova, SO Kuzin, EN Goryunova, RI Vabishchevich, AV Petrov, DV Motorin, DV Babenetskaya, VV Ivanov, KV Bogdanov, IV Kholopova, TS Nikulina, YuV Mirolyubova, YuA Alekseeva, AYu Zaritskii

VA Almazov Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Ekaterina Gennad’evna Ovsyannikova, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel: +7(921)313-68-35; e-mail: katrin51297@mail.ru

For citation: Girshova LL, Ovsyannikova EG, Kuzin SO, et al. Molecular Monitoring of RUNX1-RUNX1T1 Transcript Level in Acute Myeloblastic Leukemias on Treatment. Clinical oncohematology. 2016;9(4):456–64 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-456-464


ABSTRACT

Background. The current approach to treatment of acute myeloblastic leukemia (AML) includes the achievement of maximum tumor reduction and, therefore, eradication of a leukemic clone. The goal of the therapy is to achieve undetectable levels of the target gene, except an isolated molecular rearrangement of RUNX1-RUNX1T1.

Aim. To estimate the dynamics of the RUNX1-RUNX1T1 level and relevant clinical manifestations during the monitoring of various stages of the program therapy and after its completion.

Methods. The article presents a description of 10 cases of AML with isolated RUNX1-RUNX1T1 expression (n = 4) and the expression in combination with different molecular and cytogenetic abnormalities (= 6). In addition, a long-term monitoring of the gene expression by quantitative determination of RUNX1-RUNX1T1 using a real-time PCR was presented.

Results. The incidence of relapses in a group with a decreased RUNX1-RUNX1T1 expression level of >2 log is 75 % as compared to patients with a less significant reduction of the transcript level (with the relapse incidence equal to 0 %) (= 0.05). The increase of the RUNX1-RUNX1T1 level against the background of bone marrow remission by more than 1 log coincided with a bone marrow relapse within 5–18 weeks. In addition, long-term persistence of a certain transcript level after the completion of a program therapy without relapse is possible.

Conclusion. The study analyzed possible molecular background of different clinical outcomes of long-term persistence of the RUNX1-RUNX1T1 transcript that might lead to an individualized approach to AML patients.


Keywords: acute myeloblastic leukemia, AML, RUNX1-RUNX1T1, molecular monitoring.

Received: April 5, 2016

Accepted: April 18, 2016

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REFERENCES

  1. Bitter MA, Le Beau MM, Rowley JD, et al. Association between morphology, karyotype, and clinical features in myeloid leukemias. Hum Pathol. 1987;18(3):211–25. doi: 10.1016/s0046-8177(87)80002-3.
  2. Mrozek K, Heinonen K, de la Chapelle A, Bloomfield CD. Clinical significance of cytogenetics in acute myeloid leukemia. Semin Oncol. 1997;24(1):17–31.
  3. Rowe D, Cotterill SJ, Ross FM, et al. Cytogenetically cryptic AML1-ETO and CBFbeta-MYH11 gene rearrangement: incidence in 412 cases of acute myeloid leukaemia. Br J Haematol. 2000;111(4):1051–6. doi: 10.1111/j.1365-2141.2000.02474.x.
  4. Downing JR. AML1/CBFbeta transcription complex: its role in normal hematopoiesis and leukemia. Leukemia. 2001;15(4):664–5. doi: 10.1038/sj.leu.2402035.
  5. Рулина А.В., Спирин П.В., Прасолов В.С. Активированные лейкозные онкогены AML1-ETO и C-KIT: роль в развитии острого миелоидного лейкоза и современные подходы к их ингибированию. Успехи биологической химии. 2010;50:349–86.
    [Rulina AV, Spirin PV, Prasolov VS. Activated leukemic AML1-ETO и C-KIT oncogenes: their role in the development of acute myeloid leukemia and modern approaches to their inhibition. Uspekhi biologicheskoi khimii. 2010;50:349–86. (In Russ)]
  6. Grimwade D, Walker H, Oliver F, et al. A on behalf of the Medical Research Council Adult and Children’s Leukaemia Working Parties. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial. Blood. 1998;92(7):2322–33.
  7. Lowenberg B. Postremission treatment of acute myelogenous leukemia. N Eng J Med. 1995;332(4):260–2. doi: 10.1056/nejm199501263320411.
  8. Byrd JC, Dodge RK, Carroll A, et al. Patients with t(8;21) (q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered. J Clin Oncol. 1999;17(12):3767–75.
  9. Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100(13):4325–36. doi: 10.1182/blood-2002-03-0772.
  10. Byrd JC, Ruppert AS, Mrozek K, et al. Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16) (p13q22) or t(16;16): results from CALGB 8461. J Clin Oncol. 2004;22(6):1087–94. doi: 10.1200/jco.2004.07.012.
  11. Schlenk RF, Benner A, Krauter J, et al. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2004;22(18):3741–50. doi: 10.1200/jco.2004.03.012.
  12. Marcucci G, Mrozek K, Ruppert AS, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B Study. J Clin Oncol. 2005;23(24):5705–17. doi: 10.1200/jco.2005.15.610.
  13. Yin JAL, O’Brien MA, Hills RK, et al. Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: Results of the United Kingdom MRC AML-15 Trial. Blood. 2012;120(14):2826–35. doi: 10.1182/blood-2012-06-435669.
  14. Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood. 2013;121(12):2213–23. doi: 10.1182/blood-2012-10-462879.
  15. Byrd JC, Weiss RB, Arthur DC, et al. Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. J Clin Oncol. 1997;15(2):466–75.
  16. Nguyen S, Leblanc T, Fenaux P, et al. A white blood cell index as the main prognostic factor in t(8;21) acute myeloid leukemia (AML): a survey of 161 cases from the French AML Intergroup. Blood. 2002;99(10):3517–23. doi: 10.1182/blood.V99.10.3517.
  17. Baer MR, Stewart CC, Lawrence D, et al. Expression of the neural cell adhesion molecule CD56 is associated with short remission duration and survival in acute myeloid leukemia with t(8;21)(q22;q22). Blood. 1997;90(4):1643–8.
  18. Schoch C, Haase D, Haferlach T, et al. Fifty-one patients with acute myeloid leukemia and translocation t(8;21)(q22;q22): an additional deletion in 9q is an adverse prognostic factor. Leukemia. 1996;10(8):1288–95.
  19. Paschka P, Marcucci G, Ruppert AS, et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006;24(24):3904–11. doi: 10.1200/jco.2006.06.9500.
  20. Boissel N, Leroy H, Brethon B, et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia. 2006;20(6):965–70. doi: 10.1038/sj.leu.2404188.
  21. Hoyos M, Nomdedeu JF, Esteve J, et al. Core binding factor acute myeloid leukemia: the impact of age, leukocyte count, molecular findings, and minimal residual disease. Eur J Haematol. 2013;91(3):209–18. doi: 10.1111/ejh.12130.
  22. Демидова И.А. Использование молекулярно-биологических методов для определения генетических нарушений при миелоидных лейкозах и мониторирования минимальной остаточной болезни. Онкогематология. 2007;4:17–25.
    [Demidova IA. Application of molecular-biological methods for determining genetic disorders in myeloid leukemias and monitoring of minimal residual diseases. Onkogematologiya. 2007;4:17–25. (In Russ)]
  23. Estey EH. Acute myeloid leukemia: 2013 update on risk-stratification and management. Am J Hematol. 2013;88(4):318–27. doi: 10.1002/ajh.23404.
  24. Buccisano F, Maurillo L, Del Principe MI, et al. Prognostic and therapeutic implications of minimal residual disease detection in acute myeloid leukemia. Blood. 2012;119(2):332–41. doi: 10.1182/blood-2011-08-363291.
  25. Tobal K, Newton J, Nige S, et al. Molecular quantitation of minimal residual disease in acute myeloid leukemia with с t(8;21) can identify patients in durable remission and predict clinical relapse. Blood. 2000;95(3):815–9.
  26. Yin JAL, O’Brien MA, Hills RK, et al. Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: Results of the United Kingdom MRC AML-15 Trial. Blood. 2012;120(14):2826–30. doi: 10.1182/blood-2012-06-435669.
  27. Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood. 2013;121(12):2213–23. doi: 10.1182/blood-2012-10-462879.
  28. Zhu H-H, Zhang X-H, Qin Y-Z, et al. MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial. Blood. 2013;121(2):4056–62. doi: 10.1182/blood-2012-11-468348.
  29. Morschhauser F, Cayuela JM, Martini S, et al. Evaluation of minimal residual disease using reverse-transcription polymerase chain reaction in t(8;21) acute myeloid leukemia: a multicenter study of 51 patients. J Clin Oncol. 2000;18(4):778–94.
  30. Willekens C, Blanchet O, Renneville A, et al. Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-positive acute myeloid leukemia: results of the French CBF-2006 trial. Haematologica. 2016;101(3):328–35. doi: 10.3324/haematol.2015.131946.
  31. Schnittger S, Weisser M, Schoch C, et al. New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts. Blood. 2003;102(8):2746–55. doi: 10.1182/blood-2003-03-0880.
  32. Ommen HB, Schnittger S, Jovanovic JV, et al. Strikingly different molecular relapse kinetics in NPM1c, PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias. Blood. 2010;115(2):198–205. doi: 10.1182/blood-2009-04-212530.
  33. Krauter J, Gorlich K, Ottmann O, et al. Prognostic value of minimal residual disease quantification by real-time reverse transcriptase polymerase chain reaction in patients with core binding factor leukemias. J Clin Oncol. 2003;21(23):4413–22. doi: 10.1200/jco.2003.03.166.
  34. Marcucci G, Livak KJ, Bi W, et al. Detection of minimal residual disease in patients with AML1/ETO-associated acute myeloid leukemia using a novel quantitative reverse ttranscriptase polymerase chain reaction assay. Leukemia. 1998;12(9):1482–9. doi: 10.1038/sj.leu.2401128.
  35. Lane S, Saal R, Molle P, et al. A ³ 1 log rise in RQ-PCR transcript levels defines molecular relapse in core binding factor acute myeloid leukemia and predicts subsequent morphologic relapse. Leuk Lymphoma. 2008;49(3):517–23. doi: 10.1080/10428190701817266.
  36. Perrea G, Lasa A, Aventi A, et al. Prognostic value of minimal residual disease in acute myeloid leukemia with favorable cytogenetics [t(8.21) and inv(16)]. Leukemia. 2006;20(1):87–94. doi: 10.1038/sj.leu.2404015.
  37. Jaso JM, Wang SA, Jorgensen JL, et al. Multicolor flow cytometric immunophenotyping for detection of minimal residual disease in AML: Past, present and future. Bone Marrow Transplant. 2014;49(9):1129–38. doi: 10.1038/bmt.2014.99.
  38. Bruggermann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107(3):1116–23. doi: 10.1182/blood-2005-07-2708.
  39. Borowitz MJ, Devidas M, Hunger SP, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship in other prognostic factors: a Children’s Oncology Group Study. Blood. 2008;111(12):5477–85. doi: 10.1182/blood-2008-01-132837.
  40. Muller MC, Cross NC, Erben P, et al. Harmonisation of molecular monitoring of CML therapy in Europe. Leukemia. 2009;23(11):1957–63. doi: 10.1038/leu.2009.168.
  41. Jurlander J, Caligiuri MA, Ruutu T, et al. Persistence of the AMLI/ETO Fusion Transcript in Patients Treated With Allogeneic Bone Marrow Transplantation for t(8;21) Leukemia. Blood. 1996;88(6):2183–219.
  42. Kayser S, Schlenk RF, Grimwade D, et al. Minimal residual disease–directed therapy in acute myeloid leukemia. Blood. 2015;125(15):2331–5. doi: 10.1182/blood-2014-11-578815.
  43. Evans PA, Short MA, Jack AS, et al. Detection and quantitation of the transcripts associated with the inv(16) in presentation and follow-up samples from patients with AML. Leukemia. 1997;11(3):364–9. doi: 10.1038/sj.leu.2400578.
  44. Laczika K, Novak M, Hilgarth B, et al. Competitive CBFbeta/MYH11 reverse transcriptase polymerase chain reaction for quantitative assessment of minimal residual disease during post remission therapy in acute myeloid leukemia with inversion 16: a pilot study. J Clin Oncol. 1998;16(4):1519–25.
  45. Krauter J, Hoellge W, Wattjies MP, et al. Detection and quantitation of CBFB/MYH11 fusion transcript in patients with inv(16) positive acute myeloblastic leukemia by real-time RT-PCR. Genes Chromos Cancer. 2001;30(4):342–8. doi: 10.1002/gcc.1100.
  46. Marcucci G, Caligiuri MA, Dohner H, et al. Quantification of CBFbeta/MYH11 fusion trancript byreal-time RT-PCR in patients with inv(16) acute myeloid leukemia. Leukemia. 2001;15(7):1072–80. doi: 10.1038/sj.leu.2402159.
  47. Duployez N, Willekens C, Marceau-Renaut A, et al. Prognosis and monitoring of core-binding factor acute myeloid leukemia: current and emerging factors. Exp Rev Hematol. 2014;8(1):43–56. doi: 10.1586/17474086.2014.976551.
  48. Shima T, Miyamoto T, Kikushige Y, et al. The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell. Exp Hematol. 2014;42(11):955–65. doi: 10.1016/j.exphem.2014.07.267.
  49. Buonamici S, Ottaviani E, Visani G, et al. Patterns of AML-ETO1 transcript expression in patients with acute myeloid leukemia and t(8;21) in complete hematologic remission. Haematologica. 2004;89(1):103–5.
  50. Song J, Mercer D, Hu X, et al. Common Leukemia- and Lymphoma-Associated Genetic Aberrations in Healthy Individuals. J Mol Diagn. 2011;13(2);213–9. doi: 10.1016/j.jmoldx.2010.10.009.
  51. Miyamoto T, Weissman IL, Akashi K. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc Nat Acad Sci. 2000;97(13):7521–6. doi: 10.1073/pnas.97.13.7521.
  52. Yin JAL, Tobal K. Detection of minimal residual disease in acute myeloid leukemias: methodologies, clinical and biological significance. Br J Haematol. 1999;106(3):578–90. doi: 10.1046/j.1365-2141.1999.01522.x.
  53. Corces-Zimmerman MR, Hong W-J, Weissman IL, et al. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Nat Acad Sci. 2014;111(7):2548–53. doi: 10.1073/pnas.1324297111.
  54. Russler-Germain DA, Spencer DH, Young MA, et al. The R882H DNMT3A Mutation Associated with AML Dominantly Inhibits Wild-Type DNMT3A by Blocking Its Ability to Form Active Tetramers. Cancer Cell. 2014;25(4):442–54. doi: 10.1016/j.ccr.2014.02.010.
  55. Ommen HB, Schnittger S, Jovanovic JV, et al. Strikingly different molecular relapse kinetics in NPM1c, PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias. Blood. 2010;115(2):198–205. doi: 10.1182/blood-2009-04-212530.
  56. Wang Y, Wu D-P, Liu Q-F, et al. In adults with t(8;21) AML, posttransplant RUNX1/RUNX1T1-based MRD monitoring, rather than c-KIT mutations, allows further risk stratification. Blood. 2014;124(12):1880–6. doi: 10.1182/blood-2014-03-563403.

 

Genetic Mutations in Acute Myeloid Leukemia

OV Blau

Charite Clinic, Berlin Medical University, 30 Hindenburgdamm, Berlin, Germany, 12200

For correspondence: Ol’ga Vladimirovna Blau, DSci, Department of Hematology, Oncology and Tumorimmunology, Charite University School of Medicine, Hindenburgdamm 30, 12200, Berlin, Germany; e-mail: olga.blau@charite.de.

For citation: Blau OV. Genetic Mutations in Acute Myeloid Leukemia. Clinical oncohematology. 2016;9(3):245-56 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-245-256


ABSTRACT

Acute myeloid leukemia (AML) is a clonal malignancy characterized by ineffective hematopoiesis. Most AML patients present different cytogenetic and molecular defects associated with certain biologic and clinical features of the disease. Approximately 50–60 % of de novo AML and 80–95 % of secondary AML patients demonstrate chromosomal aberrations. Structural chromosomal aberrations are the most common cytogenetic abnormalities in about of 40 % of de novo AML patients. A relatively large group of intermediate risk patients with cytogenetically normal (CN) AML demonstrates a variety of outcomes. Current AML prognostic classifications include only some mutations with known prognostic value, namely NPM1, FLT3 and C/EBPa. Patients with NPM1 mutation, but without FLT3-ITD or C/EBPa mutations have a favorable prognosis, whereas patients with FLT3-ITD mutation have a poor prognosis. A new class of mutations affecting genes responsible for epigenetic mechanisms of genome regulations, namely for DNA methylation and histone modification, was found recently. Among them, mutations in genes DNMT3A, IDH1/2, TET2 and some others are the most well-studied mutations to date. A number of studies demonstrated an unfavorable prognostic effect of the DNMT3A mutation in AML. The prognostic significance of the IDH1/2 gene is still unclear. The prognosis is affected by a number of biological factors, including those associated with cytogenetic aberrations and other mutations, especially FLT3 and NPM1. The number of studies of genetic mutations in AML keeps growing. The data on genetic aberrations in AML obtained to date confirm their role in the onset and development of the disease.


Keywords: acute myeloid leukemia, AML, karyotype, cytogenetic aberrations, gene mutation, prognosis.

Received: January 23, 2016

Accepted: April 4, 2016

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REFERENCES

  1. Renneville A, Roumier С., Biggio V, et al. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008;22(5):915–31. doi: 10.1038/leu.2008.19.
  2. Knudson AG. Mutation and Cancer: Statistical Study of Retinoblastoma. Proc Natl Acad Sci USA. 1971;68(4):820–3. doi: 10.1073/pnas.68.4.820.
  3. Tucker T, Friedman JM. Pathogenesis of hereditary tumors: beyond the “two-hit” hypothesis. Clin Genet. 2002;62(5):345–57. doi: 10.1034/j.1399-0004.2002.620501.x.
  4. Park S, Koh Y, Yoon SS. Effects of Somatic Mutations Are Associated with SNP in the Progression of Individual Acute Myeloid Leukemia Patient: The Two-Hit Theory Explains Inherited Predisposition to Pathogenesis. Genom Inform. 2013;11(1):34–7. doi: 10.5808/gi.2013.11.1.34.
  5. Genovese G, Kahler AK, Handsaker RE, et al. Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence. N Engl J Med. 2014;371(26):2477–87. doi: 10.1056/nejmoa1409405.
  6. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11. doi: 10.1038/35102167.
  7. Grimwade D. The changing paradigm of prognostic factors in acute myeloid leukaemia. Best Pract Res Clin Haematol. 2012;25(4):419–25. 10.1016/j.beha.2012.10.004.
  8. Patel JP, Gonen M, Figueroa ME, et al. Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia. N Engl J Med. 2012;366(12):1079–89. doi: 10.1056/nejmoa1112304.
  9. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–74. doi: 10.1182/blood-2009-07-235358.
  10. Frehlick LJ, Eirin-Lopez JM, Ausio J. New insights into the nucleophosmin/nucleoplasmin family of nuclear chaperones. Bioessays. 2007;29(1):49–59. doi: 10.1002/bies.20512.
  11. Kurki S, Peltonen K, Latonen L, et al. Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cell. 2004;5(5):465–75. doi: 10.1016/s1535-6108(04)00110-2.
  12. Lindstrom MS. NPM1/B23: A Multifunctional Chaperone in Ribosome Biogenesis and Chromatin Remodeling. Biochem Res Int. 2011;2011:1–16. doi: 10.1155/2011/195209.
  13. Falini B, Bolli NI, Martelli MP, et al. Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias. 2007;92(4):519–32. doi: 10.3324/haematol.11007.
  14. Falini B, Bigerna B, Pucciarini A, et al. Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): a comparison with NPMc+ AML. Leukemia. 2006;20(2):368–71. doi: 10.1038/sj.leu.2404068.
  15. Redner R, Rush EA, Faas S, et al. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. 1996;87(3):882–6.
  16. Sportoletti P, Varasano E, Rossi R, et al. Mouse models of NPM1-mutated acute myeloid leukemia: biological and clinical implications. 2015;29(2):269–78. doi: 10.1038/leu.2014.257.
  17. Grisendi S, Mecucci C, Falini B, Pandolfi PP. Nucleophosmin and cancer. Nat Rev Cancer. 2006;6(7):493–505. doi: 10.1038/nrc1885.
  18. Sportoletti P, Grisendi S, Majid SM, et al. Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood; 2008;111(7):3859–62. doi: 10.1182/blood-2007-06-098251.
  19. Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. The Lancet. 2013;381(9865):484–95. doi: 10.1016/s0140-6736(12)61727-9.
  20. Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype. N Engl J Med. 2005;352(3):254–66. doi: 10.1056/nejmoa041974.
  21. Falini B, Martelli MP, Pileri SA, Mecucci C. Molecular and alternative methods for diagnosis of acute myeloid leukemia with mutated NPM1: flexibility may help. 2010;95(4):529–34. doi: 10.3324/haematol.2009.017822.
  22. Falini B, Albiero E, Bolli N, et al. Aberrant cytoplasmic expression of C-terminal-truncated NPM leukaemic mutant is dictated by tryptophans loss and a new NES motif. Leukemia. 2007;21(9):2052–4. doi: 10.1038/sj.leu.2404839.
  23. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909–18. doi: 10.1056/nejmoa074306.
  24. Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 Mutations Are Frequent Genetic Alterations in Acute Myeloid Leukemia and Confer Adverse Prognosis in Cytogenetically Normal Acute Myeloid Leukemia With NPM1 Mutation Without FLT3 Internal Tandem Duplication. J Clin Oncol. 2010. 28(22):3636–43. doi: 10.1200/jco.2010.28.3762.
  25. Dvorakova D, Racil Z, Jeziskova I, et al. Monitoring of minimal residual disease in acute myeloid leukemia with frequent and rare patient-specific NPM1 mutations. Am J Hematol. 2010;85(12):926–9. doi: 10.1002/ajh.21879.
  26. Schnittger S, Kern W, Tschulik C, et al. Minimal residual disease levels assessed by NPM1 mutation–specific RQ-PCR provide important prognostic information in AML. Blood. 2009;114(11):2220–31. doi: 10.1182/blood-2009-03-213389.
  27. Stahl T, Badbaran A, Kroger N, et al. Minimal residual disease diagnostics in patients with acute myeloid leukemia in the post-transplant period: comparison of peripheral blood and bone marrow analysis. Leuk Lymphoma. 2010;51(10):1837–43. doi: 10.3109/10428194.2010.508822.
  28. Kronke J, Schlenk RF, Jensen KO, et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol. 2011;29(19):2709–16. doi: 10.1200/jco.2011.35.0371.
  29. Rosnet O, Schiff C, Pebusque MJ, et al. Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. Blood. 1993;82(4):1110–9.
  30. Meshinchi S, Appelbaum FR. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res. 2009;15(13):4263–9. doi: 10.1158/1078-0432.ccr-08-1123.
  31. Sitnicka E, Buza-Vidas N, Larsson S, et al. Human CD34+ hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3: distinct flt3 and c-kit expression and response patterns on mouse and candidate human hematopoietic stem cells. Blood. 2003;102(3):881–6. doi: 10.1182/blood-2002-06-1694.
  32. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100(5):1532–42. doi: 10.1182/blood-2002-02-0492.
  33. Adolfsson J, Borge OJ, Bryder D, et al. Upregulation of Flt3 Expression within the Bone Marrow Lin–Sca1+c-kit+ Stem Cell Compartment Is Accompanied by Loss of Self-Renewal Capacity. Immunity. 2001;15(4):659–69. doi: 10.1016/s1074-7613(01)00220-5.
  34. Griffith J, Black J, Faerman C, et al. The Structural Basis for Autoinhibition of FLT3 by the Juxtamembrane Domain. Mol Cell. 2004;13(2):169–78. doi: 10.1016/s1097-2765(03)00505-7.
  35. Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111(5):2776–84. doi: 10.1182/blood-2007-08-109090.
  36. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98(6):1752–9. doi: 10.1182/blood.v98.6.1752.
  37. Marcucci G, Haferlach T, Dohner H. Molecular Genetics of Adult Acute Myeloid Leukemia: Prognostic and Therapeutic Implications. J Clin Oncol. 2011;29(5):475–86. doi: 10.1200/jco.2010.30.2554.
  38. Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. 2002;100(1):59–66. doi: 10.1182/blood.v100.1.59.
  39. Breitenbuecher F, Schnittger S, Grundler R, et al. Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor. Blood. 2009;113:4074–7. doi: 10.1182/blood-2007-11-125476.
  40. Kayser S, Schlenk RF, Londono MC, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114(12):2386–92. doi: 10.1182/blood-2009-03-209999.
  41. Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD–positive AML with respect to allogeneic transplantation. Blood. 2014;124(23):3441–9. doi: 10.1182/blood-2014-05-578070.
  42. Gu TL, Nardone J, Wang Y, et al. Survey of Activated FLT3 Signaling in Leukemia. PLoS One, 2011;6(4):e19169. doi: 10.1371/journal.pone.0019169.
  43. Rocnik JL, Okabe R, Yu JC, et al. Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood. 2006;108(4):1339–45. doi: 10.1182/blood-2005-11-011429.
  44. Blau O, Berenstein R, Sindram A, Blau IW. Molecular analysis of different FLT3-ITD mutations in acute myeloid leukemia. Leuk Lymphoma. 2013;54(1):145–52. doi: 10.3109/10428194.2012.704999.
  45. Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100(13):4372–80. doi: 10.1182/blood-2002-05-1440.
  46. Mrozek K, Marcucci G, Paschka P, et al. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood. 2007;109(2):431–48. doi: 10.1182/blood-2006-06-001149.
  47. Sengsayadeth SM, Jagasia M, Engelhardt BG, et al. Allo-SCT for high-risk AML-CR1 in the molecular era: impact of FLT3/ITD outweighs the conventional markers. Bone Marrow Transplant. 2012;47(12):1535–7. doi: 10.1038/bmt.2012.88.
  48. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97(8):2434–9. doi: 10.1182/blood.v97.8.2434.
  49. Mead AJ, Linch DC, Hills RK, et al. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood. 2007;110(4):1262–70. doi: 10.1182/blood-2006-04-015826.
  50. Whitman SP, Ruppert AS, Radmacher MD, et al. FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications. Blood. 2008;111(3):1552–9. doi: 10.1182/blood-2007-08-107946.
  51. Ozeki K, Kiyoi H, Hirose Y, et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood. 2004;103(5):1901–8. doi: 10.1182/blood-2003-06-1845.
  52. Ley TJ, Miller C, Ding L, et al. Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. N Engl J Med. 2013;368(22):2059–74. doi: 10.1056/nejmoa1301689.
  53. Gaidzik VI, Schlenk RF, Paschka P, et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). Blood. 2013;121(23):4769–77. doi: 10.1182/blood-2012-10-461624.
  54. Kottaridis PD, Gale RE, Langabeer SE, et al. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood. 2002;100(7):2393–8. doi: 10.1182/blood-2002-02-0420.
  55. Shih LY, Huang CF, Wu JH, et al. Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood. 2002;100(7):2387–92. doi: 10.1182/blood-2002-01-0195.
  56. Chu SH, Small D. Mechanisms of resistance to FLT3 inhibitors. Drug Resist Update. 2009;12(1–2):8–16. doi: 10.1016/j.drup.2008.12.001.
  57. Moore AS, Faisal A, Gonzalez de Castro D, et al. Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns. Leukemia. 2012;26(7):1462–70. doi: 10.1038/leu.2012.52.
  58. Mead AJ, Gale RE, Kottaridis PD, et al. Acute myeloid leukaemia blast cells with a tyrosine kinase domain mutation of FLT3 are less sensitive to lestaurtinib than those with a FLT3 internal tandem duplication. Br J Haematol. 2008;141(4):454–60. doi: 10.1111/j.1365-2141.2008.07025.x.
  59. Koschmieder S, Halmos B, Levantini E, Tenen DG. Dysregulation of the C/EBPa Differentiation Pathway in Human Cancer. J Clin Oncol. 2009;27(4):619–28. doi: 10.1200/jco.2008.17.9812.
  60. Wang H, Iakova P, Wilde M, et al. C/EBPa Arrests Cell Proliferation through Direct Inhibition of Cdk2 and Cdk4. Mol Cell. 2001;8(4):817–28. doi: 10.1016/s1097-2765(01)00366-5.
  61. Radomska HS, Huettner CS, Zhang P, et al. CCAAT enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol. 1998;18(7):4301–14. doi: 10.1128/mcb.18.7.4301.
  62. Zhang DE, Zhang P, Wang ND, et al. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein a-deficient mice. Proc Natl Acad Sci USA. 1997;94(2):569–74. doi: 10.1073/pnas.94.2.569.
  63. Umek RM, Friedman AD, McKnight SL. CCAAT-enhancer binding protein: a component of a differentiation switch. Science. 1991;251(4991):288–92. doi: 10.1126/science.1987644.
  64. Watkins PJ, Condreay JP, Huber BE, et al. Proliferation and tumorigenicity induced by CCAAT/enhancer-binding protein. Cancer Res. 1996;56(5):1063–7.
  65. Pabst T, Mueller BU, Zhang P, et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-[alpha] (C/EBP [alpha]), in acute myeloid leukemia. Nat Genet. 2001;27(3):263–70. doi: 10.1038/85820.
  66. Nerlov C. C/EBP [alpha] mutations in acute myeloid leukaemias. Nat Rev Cancer. 2004;4(5):394–400. doi: 10.1038/nrc1363.
  67. Wouters BJ, Jorda MA, Keeshan K, et. al. Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood. 2007;110(10):3706–14. doi: 10.1182/blood-2007-02-073486.
  68. Taskesen E, Bullinger L, Corbacioglu A, et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood. 2011;117(8):2469–75. doi: 10.1182/blood-2010-09-307280.
  69. Kirstetter P, Schuster MB, Bereshchenko O, et al. Modeling of C/EBPa Mutant Acute Myeloid Leukemia Reveals a Common Expression Signature of Committed Myeloid Leukemia-Initiating Cells. Cancer Cell. 2008;13(4):299–310. doi: 10.1016/j.ccr.2008.02.008.
  70. Shih LY, Liang DC, Huang CF, et al. AML patients with CEBP [alpha] mutations mostly retain identical mutant patterns but frequently change in allelic distribution at relapse: a comparative analysis on paired diagnosis and relapse samples. Leukemia. 2006;20(4):604–9. doi: 10.1038/sj.leu.2404124.
  71. Wouters BJ, Lowenberg B, Erpelinck-Verschueren CA, et al. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood. 2009;113(13):3088–91. doi: 10.1182/blood-2008-09-179895.
  72. Cagnetta A, Adamia S, Acharya C, et al. Role of genotype-based approach in the clinical management of adult acute myeloid leukemia with normal cytogenetics. Leuk Res. 2014;38(6):649–59. doi: 10.1016/j.leukres.2014.03.006.
  73. Wouters BJ, Sanders MA, Lugthart S, et al. Segmental uniparental disomy as a recurrent mechanism for homozygous CEBPA mutations in acute myeloid leukemia. Leukemia. 2007;21(11):2382–4. doi: 10.1038/sj.leu.2404795.
  74. Valk PJM, Verhaak RG, Beijen MA, et al. Prognostically Useful Gene-Expression Profiles in Acute Myeloid Leukemia. N Engl J Med. 2004;350(16):1617–28. doi: 10.1056/nejmoa040465.
  75. Marceau-Renaut A, Guihard S, Castaigne S, et al. Classification of CEBPA mutated acute myeloid leukemia by GATA2 mutations. Am J Hematol. 2015;90(5):E93–4. doi: 10.1002/ajh.23949.
  76. Pabst T, Mueller BU. Transcriptional dysregulation during myeloid transformation in AML. Oncogene. 2007;26(47):6829–37. doi: 10.1038/sj.onc.1210765.
  77. Frohling S, Schlenk RF, Krauter J, et al. Acute myeloid leukemia with deletion 9q within a noncomplex karyotype is associated with CEBPA loss-of-function mutations. Genes Chromos Cancer. 2005;42(4):427–32. doi: 10.1002/gcc.20152.
  78. Green CL, Koo KK, Hills RK, et al. Prognostic Significance of CEBPA Mutations in a Large Cohort of Younger Adult Patients With Acute Myeloid Leukemia: Impact of Double CEBPA Mutations and the Interaction With FLT3 and NPM1 Mutations. J Clin Oncol. 2010;28(16):2739–47. doi: 10.1200/jco.2009.26.2501.
  79. Behdad A, Weigelin HC, Elenitoba-Johnson KS, Betz BL. A Clinical Grade Sequencing-Based Assay for CEBPA Mutation Testing: Report of a Large Series of Myeloid Neoplasms. J Mol Diagn. 2015;17(1):76–84. doi: 10.1016/j.jmoldx.2014.09.007.
  80. Bienz M, Ludwig M, Leibundgut EO, et al. Risk Assessment in Patients with Acute Myeloid Leukemia and a Normal Karyotype. Clin Cancer Res. 2005;11(4):1416–24. doi: 10.1158/1078-0432.ccr-04-1552.
  81. Frohling S, Schlenk RF, Stolze I, et al. CEBPA Mutations in Younger Adults With Acute Myeloid Leukemia and Normal Cytogenetics: Prognostic Relevance and Analysis of Cooperating Mutations. J Clin Oncol. 2004;22(4):624–33. doi: 10.1200/jco.2004.06.060.
  82. Preudhomme C, Sagot C, Boissel N, et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood. 2002;100(8):2717–23. doi: 10.1182/blood-2002-03-0990.
  83. Pastore F, Kling D, Hoster E, et al. Long-term follow-up of cytogenetically normal CEBPA-mutated AML. J Hematol Oncol. 2014;7(1):55. doi: 10.1186/s13045-014-0055-7.
  84. Park SH, Chi H-S, Cho Y-U, et al. CEBPA single mutation can be a possible favorable prognostic indicator in NPM1 and FLT3-ITD wild-type acute myeloid leukemia patients with intermediate cytogenetic risk. Leuk Res. 2013;37(11):1488–94. doi: 10.1016/j.leukres.2013.08.014.
  85. Renneville A, Boissel N, Gachard N, et al. The favorable impact of CEBPA mutations in patients with acute myeloid leukemia is only observed in the absence of associated cytogenetic abnormalities and FLT3 internal duplication. Blood. 2009;113(21):5090–3. doi: 10.1182/blood-2008-12-194704.
  86. Taniuchi I, Littman DR. Epigenetic gene silencing by Runx proteins. Oncogene. 2004;23(24):4341–5. doi: 10.1038/sj.onc.1207671.
  87. Yoshida H, Kitabayashi I. Chromatin regulation by AML1 complex. Int J Hematol. 2008;87(1):19–24. doi: 10.1007/s12185-007-0004-0.
  88. Tang JL, Hou HA, Chen CY, et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. 2009;114(26):5352–61. doi: 10.1182/blood-2009-05-223784.
  89. Dicker F, Haferlach C, Sundermann J, et al. Mutation analysis for RUNX1, MLL-PTD, FLT3-ITD, NPM1 and NRAS in 269 patients with MDS or secondary AML. Leukemia. 2010;24(8):1528–32. doi: 10.1038/leu.2010.124.
  90. Gaidzik VI, Bullinger L, Schlenk RF, et al. RUNX1 Mutations in Acute Myeloid Leukemia: Results From a Comprehensive Genetic and Clinical Analysis From the AML Study Group. J Clin Oncol. 2011;29(10):1364–72. doi: 10.1200/jco.2010.30.7926.
  91. Dicker F, Haferlach C, Kern W, et al. Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia. Blood. 2007;110:1308–16. doi: 10.1182/blood-2007-02-072595.
  92. Matsuno N, Osato M, Yamashita N, et al. Dual mutations in the AML1 and FLT3 genes are associated with leukemogenesis in acute myeloblastic leukemia of the M0 subtype. Leukemia. 2003;17(12):2492–9. doi: 10.1038/sj.leu.2403160.
  93. Mendler JH, Maharry K, Becker H, et al. In rare acute myeloid leukemia patients harboring both RUNX1 and NPM1 mutations, RUNX1 mutations are unusual in structure and present in the germline. 2013;98(8):e92–4. doi: 10.3324/haematol.2013.089904.
  94. Fasan A, Haferlach C, Kohlmann A, et al. Rare coincident NPM1 and RUNX1 mutations in intermediate risk acute myeloid leukemia display similar patterns to single mutated cases. Haematologica. 2014;99(2):e20–1. doi: 10.3324/haematol.2013.099754.
  95. Fernandez-Medarde A, Santos E. Ras in Cancer and Developmental Diseases. Genes Cancer. 2011;2(3):344–58. doi: 10.1177/1947601911411084.
  96. Stites EC, Ravichandran KS. A Systems Perspective of Ras Signaling in Cancer. Clin Cancer Res. 2009;15(5):1510–3. doi: 10.1158/1078-0432.ccr-08-2753.
  97. Johnson DB, Smalley KSM, Sosman JA. Molecular Pathways: Targeting NRAS in Melanoma and Acute Myelogenous Leukemia. Clin Cancer Res. 2014;20(16):4186–92. doi: 10.1158/1078-0432.ccr-13-3270.
  98. Fedorenko IV, Gibney GT, Smalley KSM. NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene. 2013;32(25):3009–18. doi: 10.1038/onc.2012.
  99. Reuter CM, Krauter J, Onono FO, et al. Lack of noncanonical RAS mutations in cytogenetically normal acute myeloid leukemia. Ann Hematol. 2014;93(6):977–82. doi: 10.1007/s00277-014-2061-9.
  100. Bacher U, Haferlach T, Schoch C, et al. Implications of NRAS mutations in AML: a study of 2502 patients. Blood. 2006;107(10):3847–53. doi: 10.1182/blood-2005-08-3522.
  101. Padua RA, West RR. Oncogene mutation and prognosis in the myelodysplastic syndromes. Br J Haematol. 2000;111(3):873–4. doi: 10.1111/j.1365-2141.2000.02472.x.
  102. Berman JN, Gerbing RB, Alonzo TA, et al. Prevalence and clinical implications of NRAS mutations in childhood AML: a report from the Children’s Oncology Group. 2011;25(6):1039–42. doi: 10.1038/leu.2011.31.
  103. Bowen DT, Frew ME, Hills R, et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood. 2005;106(6):2113–9. doi: 10.1182/blood-2005-03-0867.
  104. Roskoski R Jr. Structure and regulation of Kit protein-tyrosine kinase–The stem cell factor receptor. Biochem Biophys Res Commun. 2005;338(3):1307–15. doi: 10.1016/j.bbrc.2005.09.150.
  105. Yarden Y, Ullrich A. Growth Factor Receptor Tyrosine Kinases. Ann Rev Biochem. 1988:57(1):443–78. doi: 10.1146/annurev.bi.57.070188.002303.
  106. Paschka P, Marcucci G, Ruppert AS, et al. Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study. J Clin Oncol. 2006;24(24):3904–11. doi: 10.1200/jco.2006.06.9500.
  107. Riera L, Marmont F, Toppino D, et al. Core binding factor acute myeloid leukaemia and c-KIT mutations. Oncol Rep. 2013;29(5):1867–72. doi: 10.3892/or.2013.2328.
  108. Cairoli R, Beghini A, Grillo G, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood. 2006;107(9):3463–8. doi: 10.1182/blood-2005-09-3640.
  109. Park SH, Chi HS, Min SK, et al. Prognostic impact of c-KIT mutations in core binding factor acute myeloid leukemia. Leuk Res. 2011;35(10):1376–83. doi: 10.1016/j.leukres.2011.06.003.
  110. Hoyos M, Nomdedeu JF, Esteve J, et al. Core binding factor acute myeloid leukemia: the impact of age, leukocyte count, molecular findings, and minimal residual disease. Eur J Haematol. 2013;91(3):209–18. doi: 10.1111/ejh.12130.
  111. Schnittger S, Kohl TM, Haferlach T, et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood. 2006;107(5):1791–9. doi: 10.1182/blood-2005-04-1466.
  112. Jiao B, Wu CF, Liang Y, et al. AML1-ETO9a is correlated with C-KIT overexpression/mutations and indicates poor disease outcome in t(8;21) acute myeloid leukemia-M2. Leukemia. 2009;23(9):1598–604. doi: 10.1038/leu.2009.104.
  113. Qin YZ, Zhu HH, Jiang Q, et al. Prevalence and prognostic significance of c-KIT mutations in core binding factor acute myeloid leukemia: A comprehensive large-scale study from a single Chinese center. Leuk Res. 2014;38(12):1435–40. doi: 10.1016/j.leukres.2014.09.017.
  114. O’Donnell MR, Tallman MS, Abboud CN, et al. Acute Myeloid Leukemia, Version 2.2013. J Natl Compr Canc Netw. 2013;11(9):1047–55.
  115. Tokumasu M, Murata C, Shimada A, et al. Adverse prognostic impact of KIT mutations in childhood CBF-AML: the results of the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial. Leukemia. 2015;29(12):2438–41. doi: 10.1038/leu.2015.121.
  116. Ito S, D’Alessio AC, Taranova OV, et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466(7310):1129–33. doi: 10.1038/nature09303.
  117. Chen Q, Chen Y, Bian C, et al. TET2 promotes histone O-GlcNAcylation during gene transcription. 2013;493(7433):561–4. doi: 10.1038/nature11742.
  118. Aslanyan M, Kroeze LI, Langemeijer SM, et al. Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial. Ann Hematol. 2014;93(8):1401–12. doi: 10.1007/s00277-014-2055-7.
  119. Chou WC, Chou SC, Liu CY, et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood. 2011;118(14):3803–10. doi: 10.1182/blood-2011-02-339747.
  120. Metzeler KH, Maharry K, Radmacher MD, et al. TET2 Mutations Improve the New European LeukemiaNet Risk Classification of Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol. 2011;29(10):1373–81. doi: 10.1200/jco.2010.32.7742.
  121. Gaidzik VI, Paschka P, Spath D, et al. TET2 Mutations in Acute Myeloid Leukemia (AML): Results From a Comprehensive Genetic and Clinical Analysis of the AML Study Group. J Clin Oncol. 2012;30(12):1350–7. doi: 10.1200/jco.2011.39.2886.
  122. Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. 2010;468(7325):839–43. doi: 10.1038/nature09586.
  123. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–67. doi: 10.1016/j.ccr.2010.11.015.
  124. Moran-Crusio K, Reavie L, Shih A, et al. Tet2 Loss Leads to Increased Hematopoietic Stem Cell Self-Renewal and Myeloid Transformation. Cancer Cell. 2011;20(1):11–24. doi: 10.1016/j.ccr.2011.06.001.
  125. Quivoron C, Couronne L, Della Valle V, et al. TET2 Inactivation Results in Pleiotropic Hematopoietic Abnormalities in Mouse and Is a Recurrent Event during Human Lymphomagenesis. Cancer Cell. 2011;20(1):25–38. doi: 10.1016/j.ccr.2011.06.003.
  126. Nibourel O, Kosmider O, Cheok M, et al. Incidence and prognostic value of TET2 alterations in de novo acute myeloid leukemia achieving complete remission. Blood. 2010;116(7):1132–5. doi: 10.1182/blood-2009-07-234484.
  127. Weissmann S, Alpermann T, Grossmann V, et al. Landscape of TET2 mutations in acute myeloid leukemia. Leukemia. 2012;26(5):934–42. doi: 10.1038/leu.2011.326.
  128. Reitman ZJ, Yan H. Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism. J Natl Cancer Inst. 2010;102(13):932–41. doi: 10.1093/jnci/djq187.
  129. Molenaar RJ, Radivoyevitch T, Maciejewski JP, et al. The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation. Biochim Biophys Acta. 2014;1846(2):326–41. doi: 10.1016/j.bbcan.2014.05.004.
  130. Emadi A, Faramand R, Carter-Cooper B, et al. Presence of isocitrate dehydrogenase (IDH) mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia (AML). Am J Hematol. 2015;90(5):E77–9. doi: 10.1002/ajh.23965.
  131. Abbas S, Lugthart S, Kavelaars FG, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood. 2010;116(12):2122–6. doi: 10.1182/blood-2009-11-250878.
  132. Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 Gene Mutations Identify Novel Molecular Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol. 2010;28(14):2348–55. doi: 10.1200/jco.2009.27.3730.
  133. Dang L, Jin S, Su SM. IDH mutations in glioma and acute myeloid leukemia. Trends Mol Med. 2010;16(9):387–97. doi: 10.1016/j.molmed.2010.07.002.
  134. Horbinski C. What do we know about IDH1/2 mutations so far, and how do we use it? Acta Neuropathol. 2013;125(5):621–36. doi: 10.1007/s00401-013-1106-9.
  135. Chotirat S, Thongnoppakhun W, Wanachiwanawin W, Auewarakul CU. Acquired somatic mutations of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) in preleukemic disorders. Blood Cells Mol Dis. 2015;54(3):286–91. doi: 10.1016/j.bcmd.2014.11.017.
  136. Green CL, Evans CM, Zhao L, et al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood. 2011;118(2):409–12. doi: 10.1182/blood-2010-12-322479.
  137. Zhou KG, Jiang LJ, Shang Z, et al. Potential application of IDH1 and IDH2 mutations as prognostic indicators in non-promyelocytic acute myeloid leukemia: a meta-analysis. Leuk Lymphoma. 2012;53(12):2423–9. doi: 10.3109/10428194.2012.695359.
  138. Marcucci G, Metzeler KH, Schwind S, et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2012;30(7):742–50. doi: 10.1200/jco.2011.39.2092.
  139. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424–33. doi: 10.1056/nejmoa1005143.
  140. Zhang Y, Chen FQ, Sun YH, et al. Effects of DNMT1 silencing on malignant phenotype and methylated gene expression in cervical cancer cells. J Exp Clin Cancer Res. 2011;30(1):98. doi: 10.1186/1756-9966-30-98.
  141. Jasielec J, Saloura V, Godley LA. The mechanistic role of DNA methylation in myeloid leukemogenesis. Leukemia. 2014;28(9):1765–73. doi: 10.1038/leu.2014.163.
  142. Li KK, Luo LF, Shen Y, et al. DNA methyltransferases in hematologic malignancies. Semin Hematol. 2013;50(1):48–60. doi: 10.1053/j.seminhematol.2013.01.005.
  143. O’Brien EC, Brewin J, Chevassut T. DNMT3A: the DioNysian MonsTer of acute myeloid leukaemia. Ther Adv Hematol. 2014;5(6):187–96. doi: 10.1177/2040620714554538.
  144. Holz-Schietinger C, Matje DM, Reich NO. Mutations in DNA methyltransferase (DNMT3A) observed in acute myeloid leukemia patients disrupt processive methylation. J Biol Chem. 2012;287(37):30941–51. doi: 10.1074/jbc.m112.366625.
  145. Russler-Germain DA, Spencer DH, Young MA, et al. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell. 2014;25(4):442–54. doi: 10.1016/j.ccr.2014.02.010146.
  146. McDevitt MA. Clinical applications of epigenetic markers and epigenetic profiling in myeloid malignancies. Semin Oncol. 2012;39(1):109–22. doi: 10.1053/j.seminoncol.2011.11.003.
  147. Berenstein R, Blau IW, Suckert N, et al. Quantitative detection of DNMT3A R882H mutation in acute myeloid leukemia. J Exp Clin Cancer Res. 2015;34(1):55. doi: 10.1186/s13046-015-0173-2.
  148. Shlush LI, Zandi S, Mitchell A, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506(7488):328–33. doi: 10.1038/nature13038.
  149. Corces-Zimmerman MR, Hong WJ, Weissman IL, et al. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci USA. 2014;111(7):2548–53. doi: 10.1073/pnas.1324297111.
  150. Thol F, Damm F, Ludeking A, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011;29(21):2889–96. doi: 10.1200/jco.2011.35.4894.
  151. Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C, et al. Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood. 2012;119(24):5824–31. doi: 10.1182/blood-2011-07-367961.
  152. Ibrahem L, Mahfouz R, Elhelw L, et al. Prognostic significance of DNMT3A mutations in patients with acute myeloid leukemia. Blood Cells Mol Dis. 2014;54(1):84–9. doi: 10.1016/j.bcmd.2014.07.015.
  153. Shivarov V, Gueorguieva R, Stoimenov A, Tiu R. DNMT3A mutation is a poor prognosis biomarker in AML: results of a meta-analysis of 4500 AML patients. Leuk Res. 2013;37(11):1445–50. doi: 10.1016/j.leukres.2013.07.032.
  154. Wakita S, Yamaguchi H, Omori I, et al. Mutations of the epigenetics-modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia. Leukemia. 2013;27(5):1044–52. doi: 10.1038/leu.2012.317.
  155. Hou HA, Kuo YY, Liu CY, et al. DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications. Blood. 2012;119(2):559–68. doi: 10.1182/blood-2011-07-369934.
  156. Ploen GG, Nederby L, Guldberg P, et al. Persistence of DNMT3A mutations at long-term remission in adult patients with AML. Br J Haematol. 2014;167(4):478–86. doi: 10.1111/bjh.13062.
  157. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98. doi: 10.1056/nejmoa1408617.