хронические миелопролиферативные заболевания

Биология миелопролиферативных новообразований

МИЕЛОИДНЫЕ ОПУХОЛИ , , , , , , ,

А.Л. Меликян, И.Н. Суборцева

ФГБУ «Гематологический научный центр» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167

Для переписки: Ирина Николаевна Суборцева, канд. мед. наук, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167; тел.: +7(495)612-44-71; e-mail: soubortseva@yandex.ru

Для цитирования: Меликян А.Л., Суборцева И.Н. Биология миелопролиферативных новообразований. Клиническая онкогематология. 2016;9(3):314-25.

DOI: 10.21320/2500-2139-2016-9-3-314-325

РЕФЕРАТ

Хронические миелопролиферативные заболевания (ВОЗ, 2001), или миелопролиферативные новообразования/опухоли (МПН) (ВОЗ, 2008), являются клональными заболеваниями, характеризуются пролиферацией одной или более клеточной линии миелопоэза в костном мозге с признаками сохраняющейся терминальной дифференцировки и, как правило, сопровождаются изменениями показателей крови. В группу классических Ph-негативных МПН отнесены истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз и МПН неклассифицируемое. Приобретенные соматические мутации, лежащие в основе патогенеза Ph-негативных МПН, представлены мутациями генов JAK2 (V617F, экзон 12), MPL, CALR. Мутации перечисленных генов наблюдаются примерно у 90 % больных. Однако данные молекулярные события не являются уникальными в патогенезе заболеваний. Мутации других генов (ТЕТ2, ASXL1, CBL, IDH1/IDH2, IKZF1, DNMT3A, SOCS, EZH2, TP53, RUNX1 и HMGA2) принимают участие в формировании фенотипа заболевания. В настоящем обзоре описываются современные представления о молекулярной биологии МПН.

Ключевые слова: хронические миелопролиферативные заболевания, миелопролиферативные новообразования, истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз, ген JAK2, ген CALR, ген MPL.

Получено: 11 апреля 2016 г.

Принято в печать: 11 апреля 2016 г.

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ЛИТЕРАТУРА

  1. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29(6):761–70. doi: 10.1200/jco.2010.31.8436.
  2. Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer. 2009;115(17):3842–7. doi: 10.1002/cncr.24440.
  3. Barosi G. Essential thrombocythemia vs. early/prefibrotic myelofibrosis: why does it matter. Best Pract Res Clin Haematol. 2014;27(2):129–40. doi: 10.1016/j.beha.2014.07.004.
  4. Vannucchi AM. Management of myelofibrosis. Am Soc Hematol Educ Program. 2011;2011(1):222–30. doi:10.1182/asheducation-2011.1.222.
  5. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895–901. doi: 10.1182/blood-2008-07-170449.
  6. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392–7. doi: 10.1200/jco.2010.32.2446.
  7. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115(9):1703–8. doi: 10.1182/blood-2009-09-245837.
  8. Tefferi A. How I treat myelofibrosis. Blood. 2011;117(13):3494–504. doi: 10.1182/blood-2010-11-315614.
  9. Tefferi A, Guglielmelli P, Lasho TL, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014;28(7):1494–500. doi: 10.1038/leu.2014.57.
  10. Agarwal MB, Malhotra H, Chakrabarti P, et al. Myeloproliferative neoplasms working group consensus recommendations for diagnosis and management of primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Indian J Med Paediatr Oncol. 2015;36(1):3–16. doi: 10.4103/0971-5851.151770.
  11. Campregher PV, Santos FP, Perini GF, Hamerschlak N. Molecular biology of Philadelphia-negative myeloproliferative neoplasms. Rev Bras Hematol Hemoter. 2012;34(2):150–5. doi: 10.5581/1516-8484.20120035.
  12. Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228(1):273–87. doi: 10.1111/j.1600-065X.2008.00754.x.
  13. Liu KD, Gaffen SL, Goldsmith MA. JAK/STAT signaling by cytokine receptors. Curr Opin Immunol. 1998;10(3):271–8. doi: 10.1016/s0952-7915(98)80165-9.
  14. Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24(6):1128–38. doi: 10.1038/leu.2010.69.
  15. Riedy MC, Dutra AS, Blake TB, et al. Genomic sequence, organization, and chromosomal localization of human JAK3. Genomics. 1996;37(1):57–61. doi: 10.1006/geno.1996.0520.
  16. Saharinen P, Silvennoinen O. The pseudokinase domain is required for suppression of basal activity of Jak2 and Jak3 tyrosine kinases and for cytokine-inducible activation of signal transduction. J Biol Chem. 2002;277(49):47954–63. doi: 10.1074/jbc.M205156200.
  17. Benekli M, Baer MR, Baumann H, Wetzler M. Signal transducer and activator of transcription proteins in leukemias. Blood. 2003;101(8):2940–54. doi: 10.1182/blood-2002-04-1204.
  18. Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA. New mutations and pathogenesis of myeloproliferative neoplasms. Blood. 2011;118(7):1723–35. doi: 10.1182/blood-2011-02-292102.
  19. Lacout C, Pisani DF, Tulliez M, et al. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood. 2006;108(5):1652–660. doi: 10.1182/blood-2006-02-002030.
  20. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–8. doi: 10.1038/nature03546.
  21. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–90. doi: 10.1056/NEJMoa051113.
  22. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387–97. doi: 10.1016/j.ccr.2005.03.023.
  23. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. The Lancet. 2005;365(9464):1054–61. doi: 10.1016/S0140-6736(05)71142-9.
  24. Butcher CM, Hahn U, To LB, et al. Two novel JAK2 exon 12 mutations in JAK2V617F-negative polycythaemia vera patients. Leukemia. 2008;22(4):870–3. doi: 10.1038/sj.leu.2404971.
  25. Jelinek J, Oki Y, Gharibyan V, et al. JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocyticleukemia. Blood. 2005;106(10):3370–3. doi: 10.1182/blood-2005-05-1800.
  26. Pich A, Riera L, Sismondi F, et al. JAK2V617F activating mutation is associated with the myeloproliferative type of chronic myelomonocytic leukaemia. J Clin Pathol. 2009;62(9):798–801. doi: 10.1136/jcp.2009.065904.
  27. Johan MF, Goodeve AC, Bowen DT, et al. JAK2 V617F Mutation is uncommon in chronic myelomonocytic leukaemia. Br J Haematol. 2005;130(6):968. doi: 10.1111/j.1365-2141.2005.05719.x.
  28. Renneville A, Quesnel B, Charpentier A, et al. High occurrence of JAK2 V617 mutation in refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Leukemia. 2006;20(11):2067–70. doi: 10.1038/sj.leu.2404405.
  29. Verstovsek S, Silver RT, Cross NC, Tefferi A. JAK2V617F mutational frequency in polycythemia vera: 100%, > 90%, less? Leukemia. 2006;20(11):2067. doi:10.1038/sj.leu.2404379.
  30. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110(3):840–6. doi: 10.1182/blood-2006-12-064287.
  31. Barosi G, Bergamaschi G, Marchetti M, et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood. 2007;110(12):4030–6. doi: 10.1182/blood-2007-07-099184.
  32. Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861–9. doi: 10.1038/leu.2013.119.
  33. Lussana F, Caberlon S, Pagani C, et al. Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review. Thromb Res. 2009;124(4):409–17. doi: 10.1016/j.thromres.2009.02.004.
  34. Wang M, He N, Tian T, et al. Mutation analysis of JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in Chinese patients with myeloproliferative neoplasms. BioMed Res Int. 2014;2014:485645. doi: 10.1155/2014/485645.
  35. Passamonti F, Thiele J, Girodon F, et al. A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment. Blood. 2012;120(6):1197–201. doi: 10.1182/blood-2012-01-403279.
  36. Barbui T, Carobbio A, Rambaldi A, Finazzi G. Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor? Blood. 2009;114(4):759–63. doi: 10.1182/blood-2009-02-206797.
  37. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120(26):5128–33. doi: 10.1182/blood-2012-07-444067.
  38. Tefferi A, Pardanani A. Myeloproliferative neoplasms – a contemporary review. JAMA Oncol. 2015;1(1):97–105. doi: 10.1001/jamaoncol.2015.89.
  39. Nussenzveig RH, Swierczek SI, Jelinek J, et al. Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol. 2007;35(1):32–8. doi: 10.1016/j.exphem.2006.11.012.
  40. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356(5):459–68. doi: 10.1056/NEJMoa065202.
  41. Williams DM, Kim AH, Rogers O, et al. Phenotypic variations and new mutations in JAK2 V617F-negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis. Exp Hematol. 2007;35(11):1641–6. doi: 10.1016/j.exphem.2007.08.010.
  42. Passamonti F, Elena C, Schnittger S, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011;117(10):2813–6. doi: 10.1182/blood-2010-11-316810.
  43. Campbell PJ, Griesshammer M, Dohner K, et al. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood. 2006;107(5):2098–100. doi: 10.1182/blood-2005-08-3395.
  44. Martinez-Aviles L, Besses C, Alvarez-Larran A, et al. JAK2 exon 12 mutations in polycythemia vera or idiopathic erythrocytosis. Haematologica. 2007;92(12):1717–8. doi: 10.3324/haematol.12011.
  45. Sangkhae V, Etheridge SL, Kaushansky K, Hitchcock IS. The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm. Blood. 2014;124(26):3956–63. doi: 10.1182/blood-2014-07-587238.
  46. Chou FS, Mulloy JC. The thrombopoietin/MPL pathway in hematopoiesis and leukemogenesis. J Cell Biochem. 2011;112(6):1491-8. doi: 10.1002/jcb.23089.
  47. Abe M, Suzuki K, Inagaki O, et al. A novel MPL point mutation resulting in thrombopoietin-independent activation. Leukemia. 2002;16(8):1500–6. doi: 10.1038/sj.leu.2402554.
  48. Ding J, Komatsu H, Wakita A, et al. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood. 2004;103(11):4198–200. doi: 10.1182/blood-2003-10-3471.
  49. Moliterno AR, Williams DM, Gutierrez-Alamillo LI, et al. Mpl Baltimore: A thrombopoietin receptor polymorphism associated with thrombocytosis. Proc Natl Acad Sci USA. 2004;101(31):11444–7. doi: 10.1073/pnas.0404241101.
  50. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270. doi: 10.1371/journal.pmed.0030270.
  51. Staerk J, Lacout C, Sato T, et al. An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor. Blood. 2006;107(5):1864–71. doi: 10.1182/blood-2005-06-2600.
  52. Boyd EM, Bench AJ, Goday-Fernandez A, et al. Clinical utility of routine MPL exon 10 analysis in the diagnosis of essential thrombocythaemia and primary myelofibrosis. Br J Haematol. 2010;149(2):250–7. doi: 10.1111/j.1365-2141.2010.08083.x.
  53. Lambert MP, Jiang J, Batra V, et al. A novel mutation in MPL (Y252H) results in increased thrombopoietin sensitivity in essential thrombocythemia. Am J Hematol. 2012;87(5):532–4. doi: 10.1002/ajh.23138.
  54. Hussein K, Bock O, Theophile K, et al. MPLW515L mutation in acute megakaryoblastic leukaemia. Leukemia. 2009;23(5):852–5. doi: 10.1038/leu.2008.371.
  55. Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood. 2008;112(1):141–9. doi: 10.1182/blood-2008-01-131664.
  56. Akpinar TS, Hancer VS, Nalcaci M, Diz-Kucukkaya R. MPL W515L/K Mutations in chronic myeloproliferative neoplasms. Turk J Haematol. 2013;30(1):8–12. doi: 10.4274/tjh.65807.
  57. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia. Blood. 2008;112(3):844–7. doi: 10.1182/blood-2008-01-135897.
  58. Teofili L, Giona F, Torti L, et al. Hereditary thrombocytosis caused by MPLSer505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. Haematologica. 2010;95(1):65–70. doi: 10.3324/haematol.2009.007542.
  59. Sun C, Zhang S, Li J. Calreticulin gene mutations in myeloproliferative neoplasms without Janus kinase 2 mutations. Leuk Lymphoma. 2015;56(6):1593–8. doi: 10.3109/10428194.2014.953153.
  60. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–90. doi: 10.1056/NEJMoa1311347.
  61. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405. doi: 10.1056/NEJMoa1312542.
  62. Shirane S, Araki M, Morishita S, et al. JAK2, CALR, and MPL mutation spectrum in Japanese myeloproliferative neoplasms patients. Haematologica. 2015;100(2):46–8. doi: 10.3324/haematol.2014.115113.
  63. Lundberg P, Karow A, Nienhold R, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014;123(14):2220–8. doi: 10.1182/blood-2013-11-537167.
  64. Lavi N. Calreticulin mutations in myeloproliferative neoplasms. Rambam Maimonides Med J. 2014;5(4):e0035. doi: 10.5041/RMMJ.10169.
  65. Rumi E, Harutyunyan AS, Pietra D, et al. CALR exon 9 mutations are somatically acquired events in familial cases of essential thrombocythemia or primary myelofibrosis. Blood. 2014;123(15):2416–9. doi: 10.1182/blood-2014-01-550434.
  66. Haslam K, Langabeer SE. Incidence of CALR mutations in patients with splanchnic vein thrombosis. Br J Haematol. 2015;168(3):459–60. doi: 10.1111/bjh.13121.
  67. Turon F, Cervantes F, Colomer D, et al. Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis. J Hepatol. 2015;62(1):72–4. doi: 10.1016/j.jhep.2014.08.032.
  68. Tefferi A, Wassie EA, Lasho TL, et al. Calreticulin mutations and long-term survival in essential thrombocythemia. Leukemia. 2014;28(12):2300–3. doi: 10.1038/leu.2014.148.
  69. Tefferi A, Lasho TL, Finke CM, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014;28(7):1472–7. doi: 10.1038/leu.2014.3.
  70. Tefferi A, Lasho TL, Finke C, et al. Type 1 vs type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact. Leukemia. 2014;28(7):1568–70. doi: 10.1038/leu.2014.83.
  71. Shide K, Kameda T, Shimoda H, et al. TET2 is essential for survival and hematopoietic stem cell homeostasis. Leukemia. 2012;26(10):2216–23. doi: 10.1038/leu.2012.94.
  72. 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.
  73. Paulsson K, Haferlach C, Fonatsch C, et al. The idic(X)(q13) in myeloid malignancies: breakpoint clustering in segmental duplications and association with TET2 mutations. Hum Mol Genet. 2010;19(8):1507–14. doi: 10.1093/hmg/ddq024.
  74. Tefferi A, Pardanani A, Lim KH, et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia. 2009;23(5):905–11. doi: 10.1038/leu.2009.47.
  75. Martinez-Aviles L, Besses C, Alvarez-Larran A, et al. TET2, ASXL1, IDH1, IDH2, and c-CBL genes in JAK2- and MPL-negative myeloproliferative neoplasms. Ann Hematol. 2012;91(4):533–41. doi: 10.1007/s00277-011-1330-0.
  76. Patriarca A, Colaizzo D, Tiscia G, et al. TET2 mutations in Ph-negative myeloproliferative neoplasms: identification of three novel mutations and relationship with clinical and laboratory findings. BioMed Res Int. 2013;2013:929840. doi: 10.1155/2013/929840.
  77. Schaub FX, Looser R, Li S, et al. Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms. Blood. 2010;115(10):2003–7. doi: 10.1182/blood-2009-09-245381.
  78. 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.
  79. Beer PA, Delhommeau F, LeCouedic JP, et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood. 2010;115(14):2891–900. doi: 10.1182/blood-2009-08-236596.
  80. Ortmann CA, Kent DG, Nangalia J, et al. Effect of mutation order on myeloproliferative neoplasms. N Engl J Med. 2015;372(7):601–12. doi: 10.1056/NEJMoa1412098.
  81. 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.
  82. Carbuccia N, Murati A, Trouplin V, et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia. 2009;23(11):2183–6. doi: 10.1038/leu.2009.141.
  83. Carbuccia N, Trouplin V, Gelsi-Boyer V, et al. Mutual exclusion of ASXL1 and NPM1 mutations in a series of acute myeloid leukemias. Leukemia. 2010;24(2):469–73. doi: 10.1038/leu.2009.218.
  84. Abdel-Wahab O, Adli M, LaFave LM, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012;22(2):180–93. doi: 10.1016/j.ccr.2012.06.032.
  85. Brecqueville M, Rey J, Bertucci F, et al. Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms. Genes Chromos Cancer. 2012;51(8):743–55. doi: 10.1002/gcc.21960.
  86. Katoh M. Functional and cancer genomics of ASXL family members. Br J Cancer. 2013;109(2):299–306. doi: 10.1038/bjc.2013.281.
  87. Cervantes F. How I treat myelofibrosis. Blood. 2014;124(17):2635–42. doi: 10.1182/blood-2014-07-575373.
  88. Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42(8):722–6. doi: 10.1038/ng.621.
  89. Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res. 2008;647(1–2):21–9. doi: 10.1016/j.mrfmmm.2008.07.010.
  90. Im AP, Sehgal AR, Carroll MP, et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia. 2014;28(9):1774–83. doi: 10.1038/leu.2014.124.
  91. Walter MJ, Ding L, Shen D, et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia. 2011;25(7):1153–8. doi: 10.1038/leu.2011.44.
  92. Yamashita Y, Yuan J, Suetake I, et al. Array-based genomic resequencing of human leukemia. Oncogene. 2010;29(25):3723–31. doi: 10.1038/onc.2010.117.
  93. Abdel-Wahab O, Pardanani A, Rampal R, et al. DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms. Leukemia. 2011;25(7):1219–20. doi: 10.1038/leu.2011.82.
  94. Brecqueville M, Cervera N, Gelsi-Boyer V, et al. Rare mutations in DNMT3A in myeloproliferative neoplasms and myelodysplastic syndromes. Blood Cancer J. 2011;1(5):e18. doi: 10.1038/bcj.2011.15.
  95. Rudd CE. Lnk adaptor: novel negative regulator of B cell lymphopoiesis. Sci STKE. 2001;2001(85):pe1. doi: 10.1126/stke.2001.85.pe1.
  96. Gery S, Cao Q, Gueller S, et al. Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F. J Leuk Biol. 2009;85(6):957–65. doi: 10.1189/jlb.0908575.
  97. Soriano G, Heaney M. Polycythemia vera and essential thrombocythemia: new developments in biology with therapeutic implications. Curr Opin Hematol. 2013;20(2):169–75. doi: 10.1097/MOH.0b013e32835d82fe.
  98. Oh ST, Simonds EF, Jones C, et al. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood. 2010;116(6):988–92. doi: 10.1182/blood-2010-02-270108.
  99. Lasho TL, Pardanani A, Tefferi A. LNK mutations in JAK2 mutation-negative erythrocytosis. N Engl J Med. 2010;363(12):1189–90. doi: 10.1056/NEJMc1006966.
  100. Rathinam C, Thien CB, Flavell RA, Langdon WY. Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling. Cancer Cell. 2010;18(4):341–52. doi: 10.1016/j.ccr.2010.09.008.
  101. Loh ML, Sakai DS, Flotho C, et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood. 2009;114(9):1859–63. doi: 10.1182/blood-2009-01-198416.
  102. Sanada M, Suzuki T, Shih LY, et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature. 2009;460(7257):904–8. doi: 10.1038/nature08240.
  103. Zhang MY, Fung TK, Chen FY, Chim CS. Methylation profiling of SOCS1, SOCS2, SOCS3, CISH and SHP1 in Philadelphia-negative myeloproliferative neoplasm. J Cell Mol Med. 2013;17(10):1282–90. doi: 10.1111/jcmm.12103.
  104. Fourouclas N, Li J, Gilby DC, et al. Methylation of the suppressor of cytokine signaling 3 gene (SOCS3) in myeloproliferative disorders. Haematologica. 2008;93(11):1635–44. doi: 10.3324/haematol.13043.
  105. Kastner P, Chan S. Role of Ikaros in T-cell acute lymphoblastic leukemia. World J Biol Chem. 2011;2(6):108–14. doi: 10.4331/wjbc.v2.i6.108.
  106. Jager R, Kralovics R. Molecular pathogenesis of Philadelphia chromosome negative chronic myeloproliferative neoplasms. Curr Cancer Drug Targets. 2011;11(1):20–30. doi: 10.2174/156800911793743628.
  107. Ikeda K, Ogawa K, Takeishi Y. The role of HMGA2 in the proliferation and expansion of a hematopoietic cell in myeloproliferative neoplasms. Fukushima J Med Sci. 2012;58(2):91–100. doi: 10.5387/fms.58.91.
  108. Harada-Shirado K, Ikeda K, Ogawa K, et al. Dysregulation of the MIRLET7/HMGA2 axis with methylation of the CDKN2A promoter in myeloproliferative neoplasms. Br J Haematol. 2015;168(3):338–49. doi: 10.1111/bjh.13129.
  109. Raza S, Viswanatha D, Frederick L, et al. TP53 mutations and polymorphisms in primary myelofibrosis. Am J Hematol. 2012;87(2):204–6. doi: 10.1002/ajh.22216.
  110. Lu M, Hoffman R. p5 as a target in myeloproliferative neoplasms. Oncotarget. 2012;3(10):1052–3. doi: 10.18632/oncotarget.719.
  111. Gurney AL, Wong SC, Henzel WJ, de Sauvage FJ. Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation. Proc Natl Acad Sci USA. 1995;92(12):5292–6. doi: 10.1073/pnas.92.12.5292
  112. Tefferi A, Thiele J, Vannucchi AM, Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia. 2014;28(7):1407–13. doi: 10.1038/leu.2014.35.
  113. Broseus J, Park JH, Carillo S, et al. Presence of calreticulin mutations in JAK2-negative polycythemia vera. Blood. 2014;124(26):3964–6. doi: 10.1182/blood-2014-06-583161.
  114. Hasan S, Lacout C, Marty C, et al. JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNa. Blood. 2013;122(8):1464–77. doi: 10.1182/blood-2013-04-498956.
  115. Pardanani A, Lasho T, Finke C, et al. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations. Leukemia. 2010;24(10):1713–8. doi: 10.1038/leu.2010.163.

Новые маркеры прогрессирования хронического миелолейкоза

КЛИНИКА, ДИАГНОСТИКА И ЛЕЧЕНИЕ МИЕЛОИДНЫХ ОПУХОЛЕЙ , , ,

В.А. Мисюрин1,2, А.В. Мисюрин1,2, Л.А. Кесаева1,2, Ю.П. Финашутина1,2, Е.Н. Мисюрина2, И.Н. Солдатова1,2, А.А. Крутов2, Н.А. Лыжко1,2, Т.В. Ахлынина2, А.Е. Лукина3, Т.И. Колошейнова3, Н.В. Новицкая1, Е.Г. Аршанская4, Е.Г. Овсянникова5, Р.А. Голубенко6, В.А. Лапин7, Т.И. Поспелова8, В.А. Тумаков9, А.Ю. Барышников1

1 ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» РАМН, Москва, Российская Федерация

2 Медицинский центр ООО «ГеноТехнология», Москва, Российская Федерация

3 ФГБУ «Гематологический научный центр» МЗ РФ, Москва, Российская Федерация

4 Московский гематологический городской центр при ГКБ им. С.П. Боткина, Москва, Российская Федерация

5 Астраханская государственная медицинская академия, Астрахань, Российская Федерация

6 Орловская областная клиническая больница, Орел, Российская Федерация

7 Гематологический центр ЯОКБ № 1, Ярославль, Российская Федерация

8 Новосибирский государственный медицинский университет, Новосибирск, Российская Федерация

9 Ивановская ОКБ № 1, Иваново, Российская Федерация

РЕФЕРАТ

Хронический миелоидный лейкоз (ХМЛ) отличается от Ph-негативных хронических миелопролиферативных заболеваний (хМПЗ) относительно более ранней трансформацией в поздние стадии, известные как фаза акселерации (ФА) и бластный криз (БК). В классификации ВОЗ 2008 г. хМПЗ обозначены как миелопролиферативные опухоли. Молекулярные механизмы прогрессии ХМЛ в настоящее время только начинают проясняться. Недавно было показано, что прогрессия некоторых злокачественных опухолей сопровождается активацией так называемых раково-тестикулярных генов (РТГ). Данная работа посвящена исследованию профиля экспрессии РТГ: GAGE1, NY-ESO-1, MAGEA1, SCP1, SEMG1, SPANXA1, SSX1 и PRAME — в крови первичных больных хМПЗ, а также в крови и костном мозге пациентов с ХМЛ в хронической фазе, ФА и БК. В результате проведенного исследования была обнаружена достоверная связь перехода ХМЛ в ФА и БК с активацией экспрессии данных генов.

Ключевые слова: раково-тескикулярные гены, PRAME, экспрессия генов, хронический миелоидный лейкоз, хронические миелопролиферативные заболевания.

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ЛИТЕРАТУРА

  1. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood 1951; 6(4): 372–5.
  2. Tefferi A., Vainchenker W. Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J. Clin. Oncol. 2011; 29(5): 573–82.
  3. Rowley J.D. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and giemsa staining. Nature 1973; 243(5405): 290–3.
  4. Scott L.M., Tong W., Levine R.L. et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N. Engl. J. Med. 2007; 356(5): 459–68.
  5. Gabler K., Behrmann I., Haan C. JAK2 mutants (e.g., JAK2V617F) and their importance as drug targets in myeloproliferative neoplasms. JAKSTAT 2013; 2(3): 250–5.
  6. Deininger M.W., Goldman J.M., Melo J.V. The molecular biology of chronic myeloid leukemia. Blood 2000; 96(10): 3343–56.
  7. Мисюрин А.В. Молекулярный патогенез миелопролиферативных за- болеваний. Клин. онкогематол. 2009; 2(3): 201–9. [Misyurin A.V. Molecular pathogenesis of myeloproliferative disorders. Klin. onkogematol. 2009; 2(3): 201–9. (In Russ.)].
  8. Tutaeva V., Misurin A.V., RoZenberg J.M. et al. Application of prv-1 mrna expression level and Jak2v617f mutation for the differentiating between polycytemia vera and secondary erythrocytosis and assessment of treatment by interferon or hydroxyurea. Hematology 2007; 12(6): 473–9.
  9. Heaney M.L., Soriano G. Acute myeloid leukemia following a myeloproliferative neoplasm: clinical characteristics, genetic features and effects of therapy. Curr. Hematol. Malig. Rep. 2013; 8(2): 116–22.
  10. Turkina A.G., Zabotina T.N., Kusnetzov S.V. et al. Studies of some mechanisms of drug resistence in chronic myeloid leukemia (CML). Adv. Exper. Med. Biol. 1999; 457: 477–88.
  11. Kremenetskaya O.S., Logacheva N.P., Baryshnikov A.Y. et al. Distinct effects of various p53 mutants on differentiation and viability of human K562 leukemia cells. Oncol. Res. 1997; 9: 155–66.
  12. Turkina A.G., Baryshnikov A.Y., Sedyakhina N.P. et al. Studies of Pglycoprotein in chronic myelogenous leukaemia patients: Expression, activity and correlations with CD34 antigen. Br. J. Haematol. 1996; 92: 88–96.
  13. Stavrovskaya A.A., Sedyakhina N.P., Stromskaya T. et al. Prognastic value of P-glicoprotein and correlation with CD34 antigen. Br. J. Heamatol. 1998; 28(5–6): 469–82.
  14. Барышников А.Ю. Взаимодействие опухоли и иммунной системы организма. Практ. онкол. 2003; 4(3): 127–30. [Baryshnikov A.Yu. Interaction between tumor and immune system. Prakt. onkol. 2003; 4(3): 127–30. (In Russ.)].
  15. Барышников А.Ю. Принципы и практика вакцинотерапии рака. Бюл. СО РАМН 2004; 2: 59–63. [Baryshnikov A.Yu. Principles and practice of cancer vaccine-prophylaxis. Byul. SO RAMN 2004; 2: 59–63. (In Russ.)].
  16. Барышников А.Ю., Демидов Л.В., Михайлова И.Н., Петенко Н.Н. Современные проблемы биотерапии опухолей. Вестн. Моск. онкол. общ. 2008; 1: 6–10. [Baryshnikov A.Yu., Demidov L.V., Mikhaylova I.N., Petenko N.N. Current issues of biotherapy for tumors. Vestn. Mosk. onkol. obshch. 2008; 1: 6–10. (In Russ.)]. 17. Michailova I.N., Morozova L.Ph., Golubeva V.A. et al. Cancer/testis genes expression in human melanoma cell lines. Melanoma Res. 2008; 18(5): 303–13.
  17. Turkina A.G., Logacheva N.P., Stromskaya T.P. et al. Studies of some mechanisms of drug resistance in chronic myeloid leukemia (CML). 3rd International Symposium on Drug Resistance in Leukemia and Lymphoma. Amsterdam, 1998. Drug resistance in leukemia and lymphoma III Book Series: advances in experimental medicine and biology. Ed. by G.J.L. Kaspers, R. Pieters, A.J.P. Veerman. 1999: 457, 477–88.
  18. Lim S.H., Zhang Y., Zhang J. Cancer-testis antigens: the current status on antigen regulation and potential clinical use. Am. J. Blood Res. 2012; 2(1): 29–35.
  19. Гапонова Т.В., Менделеева Л.П., Мисюрин А.В., Варламова Е.В., Савченко В.Г. Экспрессия опухолеассоциированных генов PRAME, WT1 и XIAP у больных множественной миеломой. Онкогематол. 2009; 2: 52–7. [Gaponova T.V., Mendeleyeva L.P., Misyurin A.V., Varlamova Ye.V., Savchenko V.G. Expression of PRAME, WT1 and XIAP tumor-associated genes in patients with multiple myeloma. Onkogematol. 2009; 2: 52–7. (In Russ.)].
  20. Абраменко И.В., Белоус Н.И., Крячок И.А. и др. Экспрессия гена PRAME при множественной миеломе. Тер. арх. 2004; 7: 77–81. [Abramenko I.V., Belous N.I., Kryachok I.A., et al. Expression of PRAME gene in multiple myeloma. Ter. arkh. 2004; 7: 77–81. (In Russ.)].
  21. Radich J.P., Dai H., Mao M. et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc. Natl. Acad. Sci. U S A 2006; 103(8): 2794–9.
  22. Демидова И.А., Савченко В.Г., Ольшанская Ю.В. и др. Аллогенная трансплантация костного мозга после режимов кондиционирования по- ниженной интенсивности в терапии больных гемобластозами. Тер. арх. 2003; 75(7): 15–21. [Demidova I.A., Savchenko V.G., Olshanskaya Yu.V., et al. Allogeneic bone martrow transplantation after reduced-intensity conditioning regimens in management of patients with hematological malignancies. Ter. arkh. 2003; 75(7): 15–21. (In Russ.)].
  23. Anguille S., Van Tendeloo V.F., Berneman Z.N. Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia. Leukemia 2012; 26(10): 2186–96.
  24. Lichtenegger F.S., Schnorfeil F.M., Hiddemann W., Subklewe M. Current strategies in immunotherapy for acute myeloid leukemia. Immunotherapy 2013; 5(1): 63–78.