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

MYELOID TUMORS , ,

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 (n = 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 %) (p = 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

Read in PDF (RUS)pdficon

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.