Цитогенетические и молекулярно-генетические факторы прогноза острых миелоидных лейкозов

ОБЗОРЫ , , , ,

А.В. Мисюрин

ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России, Каширское ш., д. 24, Moсква, Российская Федерация, 115478

Для переписки: Андрей Витальевич Мисюрин, канд. биол. наук, Каширское ш., д. 24, Moсква, Российская Федерация, 115478; e-mail: and@genetechnology.ru

Для цитирования: Мисюрин А.В. Цитогенетические и молекулярно-генетические факторы прогноза острых миелоидных лейкозов. Клиническая онкогематология. 2017;10(2):227–34.

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

РЕФЕРАТ

В обзоре приведены данные о диагностическом и прогностическом значении цитогенетических и молекулярно-генетических маркеров острых миелоидных лейкозов (ОМЛ). Показано, что в ряде случаев выделенные ранее на основе клинико-морфоцитохимических характеристик варианты ОМЛ можно разграничить благодаря обнаружению специфических генетических и хромосомных дефектов. Тем не менее, некоторые одинаковые повторяющиеся хромосомные аномалии могут быть обнаружены у больных ОМЛ, заболевание у которых согласно клинико-морфоцитохимическим признакам можно отнести к разным вариантам миелоидного лейкоза. В настоящее время признается, что изменение кариотипа является определяющим фактором прогноза, имеющим более существенное значение, чем критерии, основанные на морфологических и цитохимических признаках. В связи с этим выбор риск-адаптированной программы лечения ОМЛ следует проводить с учетом результатов цитогенетического исследования. В обзоре особый раздел посвящен известным к настоящему времени мутациям генов, которые могут влиять на результаты лечения ОМЛ.

Ключевые слова: ОМЛ, хромосомная аномалия, химерный онкоген, экспрессия гена, мутация гена.

Получено: 16 сентября 2016 г.

Принято в печать: 3 января 2017 г.

Читать статью в PDFpdficon

ЛИТЕРАТУРА

  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)]