【摘要】 近年来大量的研究对骨髓增殖性疾病发病机制有了更进一步的认识。其中最重要的发现是出现在绝大多数阵型红细胞增多症和一半左右原发性血小板增多症及骨髓纤维化的JAK2 V617F突变，能使细胞增殖活性明显增强，并引起细胞的增殖和凋亡抑制。其他的突变包括JAK2外显子12突变、MPL突变等。对慢性粒细胞白血病的急变机制及对伊马替尼的耐药机制也有了更多的认识。这些新的发现影响了慢性骨髓增殖性肿瘤的诊断标准与流程，并对其治疗提供了新的靶点。
Citation： 郭海鹰. 骨髓增殖性肿瘤发病机制的研究进展及临床应用. West China Medical Journal, 2011, 26(12): 1798-1804. doi: Copy
| 1. | Tefferi A, Vardiman Jw. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms[J]. Leukemia, 2008, 22(1): 14-22. |
| 2. | James C, Ugo V, LE COUEDIC, et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythemia vera [J]. Nature, 2005, 434(7037): 1144-1148. |
| 3. | Dalal I, Arpaia E, Dadi H, et al. Cloning and characterization of the human homolog of mouse Jak2[J]. Blood, 1998, 91(3): 844-851. |
| 4. | Baxter EJ, Seott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders [J]. Lancet, 2005, 365(9464): 1054-1061. |
| 5. | Zeuner A, Pedini F, Signore M, et al. Increased death receptor resistance and FLIP short expression in polycythemia vera erythroid precursor cells[J]. Blood, 2006, 107(9): 3459-3502. |
| 6. | Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis[J]. N Engl J Med, 2007, 356(5): 459-468. |
| 7. | Pardanani AD, Levine RL, Lasho T, et al. MPL 515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients[J]. Blood, 2006, 108(10): 3472-3476. |
| 8. | Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia[J]. PLoS Med, 2006, 3(7): 270. |
| 9. | Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort[J]. Blood, 2008, 112(1): 141-149. |
| 10. | Vannucchi AM, Antonioli E, Guglielmelli P, et al. Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia[J]. Blood, 2008, 112(3): 844-847. |
| 11. | Guglielmelli P, Pancrazzi A, Berganaschi G, et al. Anemia characterizes patients with myelofibrosis harboring MPL mutation[J]. Br J Haematol, 2007, 137(3): 244-247. |
| 12. | 吴迪炯, 孙洁, 周郁鸿, 等. 骨髓增殖性疾病的认知和治疗[J]. 国际输血及血液学杂志, 2010, 33(3): 276-279. |
| 13. | Cortes JE, Talpaz M, Kantarjian H. Chronic myelogenous leukemia: a review [J]. Am J Med, 1996, 100(5): 555-570. |
| 14. | Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia[J]. N Engl J Med, 2002, 346(9): 645-652. |
| 15. | 高素君, 朱迅, 姚程, 等. 慢性髓系白血病不同病期基因表达谱研究[J]. 中国试验血液学杂志, 2010, 18(3): 575-578. |
| 16. | 陈颖, 戴敏, 马萍. 慢性粒细胞白血病发病机制的研究进展[J]. 现代临床医学, 2009(35): 163-164. |
| 17. | Griesshammer M, Heinze B, Bangerter M, et al. Karyotype abnormalities and their clinical significance in blastcrisis of chronic myeloid leukemia[J]. J Mol Med, 1997, 75(11-12): 836-838. |
| 18. | Johansson B, Fioretos T, M itelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia[J]. Acta Haematol, 2002, 107(2): 76-94. |
| 19. | 陈志妹, 金洁, 楼基余, 等. 慢性粒细胞白血病353例的染色体核型分析[J]. 中华内科杂志, 2002, 41(6): 414. |
| 20. | Cuenco GM, Ren R. Cooperation of BCR-ABL and AML1 /MDS1 /EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia [J]. Oncogene, 2001, 20(57): 8236-8248. |
| 21. | Dash AB, W illiams IR, Kutok JL, et al. A murine model of CML blast crisis induced by cooperation between BCR /ABL and NUP98 /HOXA9 [J]. Proc Natl Acad Sci USA, 2002, 99(11): 7622-7627. |
| 22. | Feinstein E, Cimino G, Gale RP, et al. p53 in chronic myelogenous leukemia in acute phase [J]. Proc Natl Acad Sci USA, 1991, 88(14): 6293-6297. |
| 23. | Sill H, Goldman JM, Cross NC. Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia [J]. Blood, 1995, 85(8): 2013-2016. |
| 24. | Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia [J]. Acta Haematol, 2002, 107(2): 76-94. |
| 25. | Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders [J]. Lancet, 2005, 365(9464): 1054-1061. |
| 26. | Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders [J]. N Engl J Med, 2005, 352(17): 1779-1790. |
| 27. | James C,Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera [J]. Nature, 2005, 434(7037): 1144-1148. |
| 28. | Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes [J]. Blood, 2005, 106(4): 1207-1209. |
| 29. | James C, Delhommeau F, Marzac C, et al. Detection of JAK2V617F as a first intention diagnostic test for erythrocytosis [J]. Leukemia, 2006, 20(2): 350-353. |
| 30. | Mossuz P, Girodon F, Donnard M, et al. Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis [J]. Haematologica, 2004, 89(10): 1194-1198. |
| 31. | 于亚平. 骨髓增生肿瘤WHO2008修订分类及临床诊断方法[J]. 现代肿瘤医学, 2009(17): 743-747. |
| 32. | Tefferi A, Gilliland DG. The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis [J]. Mayo Clin Proc, 2005, 80(7): 947-958. |
| 33. | Campbell PJ, Linda MS, Georgina B, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study [J]. Lancet, 2005, 366(9501): 1945-1953. |
| 34. | Anthony JB, Heike LP. Chromosome abnormalities and molecular markers in myeloprolificative disorders [J]. Semin Hematol, 2005, 42(4): 196-205. |
| 35. | Thiele J, Kvasnicka HM. Clinicopathological criteria for differential diagnosis of thrombocythemias in various myeloproliferative disorders [J]. Semin Thromb Hemost, 2006, 32(3): 219-230. |
| 36. | Tefferi A, Pardanani A. Mutation screening for JAK2V617F: when to order the test and how to interpret the results [J]. Leuk Res, 2006, 30(6): 739-744. |
| 37. | Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms [J]. Leukemia, 2008, 22(1): 14-22. |
| 38. | Mesa R, Verstovsek S, Cervantes F, et al. Primary myelofibrosis(PMF), post polycythemia vera myelofibrosis(post-PV MF), post essential thrombocythemia myelofibrosis(post-ETMF), blast phase PMF(PMF-BP): Consensus on terminology by the International Working Group for Myelofibrosis Research and Treatment(IWGMRT)[J]. Leukemia Res, 2007, 31(6): 737-740. |
| 39. | Girodon F, Bonicelli G, Schaeffer C, et al. Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: population-based study [J]. Haematologica, 2009, 94(6): 865-869. |
| 40. | Dingli D, Grand FH, Mahaffey V, et al. Der(6)t(1;6)(q21-23; p21.3): a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia [J]. Br J Haematol, 2005, 130(2): 229-232. |
| 41. | 赖永榕. 真性红细胞增多症的诊断和治疗[J]. 内科危急重症杂志, 2009, 15(2): 66-73. |
| 42. | 洪鸣, 徐卫, 李建勇. 原发性骨髓纤维化的诊断和鉴别诊断[J]. 内科危急重症杂志, 2009(15): 68-70. |
| 43. | Verstovsek S, Pardanani AD, Shah NP, et al. A phaseⅠstduy of XL019, a selective JAK2inhibitor, in patients with primary myelofibrosis and post-polycythemia vera/essential thrombocythemia myelofibrosis[J]. Blood, 2007, 110. |
| 44. | Levine R, Heaney M. New advances in the pathogenesis and therapy of essential thrombocythemia[J]. Hematology, 2008, 207(1): 76-82. |
- 1. Tefferi A, Vardiman Jw. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms[J]. Leukemia, 2008, 22(1): 14-22.
- 2. James C, Ugo V, LE COUEDIC, et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythemia vera [J]. Nature, 2005, 434(7037): 1144-1148.
- 3. Dalal I, Arpaia E, Dadi H, et al. Cloning and characterization of the human homolog of mouse Jak2[J]. Blood, 1998, 91(3): 844-851.
- 4. Baxter EJ, Seott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders [J]. Lancet, 2005, 365(9464): 1054-1061.
- 5. Zeuner A, Pedini F, Signore M, et al. Increased death receptor resistance and FLIP short expression in polycythemia vera erythroid precursor cells[J]. Blood, 2006, 107(9): 3459-3502.
- 6. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis[J]. N Engl J Med, 2007, 356(5): 459-468.
- 7. Pardanani AD, Levine RL, Lasho T, et al. MPL 515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients[J]. Blood, 2006, 108(10): 3472-3476.
- 8. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia[J]. PLoS Med, 2006, 3(7): 270.
- 9. Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort[J]. Blood, 2008, 112(1): 141-149.
- 10. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia[J]. Blood, 2008, 112(3): 844-847.
- 11. Guglielmelli P, Pancrazzi A, Berganaschi G, et al. Anemia characterizes patients with myelofibrosis harboring MPL mutation[J]. Br J Haematol, 2007, 137(3): 244-247.
- 12. 吴迪炯, 孙洁, 周郁鸿, 等. 骨髓增殖性疾病的认知和治疗[J]. 国际输血及血液学杂志, 2010, 33(3): 276-279.
- 13. Cortes JE, Talpaz M, Kantarjian H. Chronic myelogenous leukemia: a review [J]. Am J Med, 1996, 100(5): 555-570.
- 14. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia[J]. N Engl J Med, 2002, 346(9): 645-652.
- 15. 高素君, 朱迅, 姚程, 等. 慢性髓系白血病不同病期基因表达谱研究[J]. 中国试验血液学杂志, 2010, 18(3): 575-578.
- 16. 陈颖, 戴敏, 马萍. 慢性粒细胞白血病发病机制的研究进展[J]. 现代临床医学, 2009(35): 163-164.
- 17. Griesshammer M, Heinze B, Bangerter M, et al. Karyotype abnormalities and their clinical significance in blastcrisis of chronic myeloid leukemia[J]. J Mol Med, 1997, 75(11-12): 836-838.
- 18. Johansson B, Fioretos T, M itelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia[J]. Acta Haematol, 2002, 107(2): 76-94.
- 19. 陈志妹, 金洁, 楼基余, 等. 慢性粒细胞白血病353例的染色体核型分析[J]. 中华内科杂志, 2002, 41(6): 414.
- 20. Cuenco GM, Ren R. Cooperation of BCR-ABL and AML1 /MDS1 /EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia [J]. Oncogene, 2001, 20(57): 8236-8248.
- 21. Dash AB, W illiams IR, Kutok JL, et al. A murine model of CML blast crisis induced by cooperation between BCR /ABL and NUP98 /HOXA9 [J]. Proc Natl Acad Sci USA, 2002, 99(11): 7622-7627.
- 22. Feinstein E, Cimino G, Gale RP, et al. p53 in chronic myelogenous leukemia in acute phase [J]. Proc Natl Acad Sci USA, 1991, 88(14): 6293-6297.
- 23. Sill H, Goldman JM, Cross NC. Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia [J]. Blood, 1995, 85(8): 2013-2016.
- 24. Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia [J]. Acta Haematol, 2002, 107(2): 76-94.
- 25. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders [J]. Lancet, 2005, 365(9464): 1054-1061.
- 26. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders [J]. N Engl J Med, 2005, 352(17): 1779-1790.
- 27. James C,Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera [J]. Nature, 2005, 434(7037): 1144-1148.
- 28. Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes [J]. Blood, 2005, 106(4): 1207-1209.
- 29. James C, Delhommeau F, Marzac C, et al. Detection of JAK2V617F as a first intention diagnostic test for erythrocytosis [J]. Leukemia, 2006, 20(2): 350-353.
- 30. Mossuz P, Girodon F, Donnard M, et al. Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis [J]. Haematologica, 2004, 89(10): 1194-1198.
- 31. 于亚平. 骨髓增生肿瘤WHO2008修订分类及临床诊断方法[J]. 现代肿瘤医学, 2009(17): 743-747.
- 32. Tefferi A, Gilliland DG. The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis [J]. Mayo Clin Proc, 2005, 80(7): 947-958.
- 33. Campbell PJ, Linda MS, Georgina B, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study [J]. Lancet, 2005, 366(9501): 1945-1953.
- 34. Anthony JB, Heike LP. Chromosome abnormalities and molecular markers in myeloprolificative disorders [J]. Semin Hematol, 2005, 42(4): 196-205.
- 35. Thiele J, Kvasnicka HM. Clinicopathological criteria for differential diagnosis of thrombocythemias in various myeloproliferative disorders [J]. Semin Thromb Hemost, 2006, 32(3): 219-230.
- 36. Tefferi A, Pardanani A. Mutation screening for JAK2V617F: when to order the test and how to interpret the results [J]. Leuk Res, 2006, 30(6): 739-744.
- 37. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms [J]. Leukemia, 2008, 22(1): 14-22.
- 38. Mesa R, Verstovsek S, Cervantes F, et al. Primary myelofibrosis(PMF), post polycythemia vera myelofibrosis(post-PV MF), post essential thrombocythemia myelofibrosis(post-ETMF), blast phase PMF(PMF-BP): Consensus on terminology by the International Working Group for Myelofibrosis Research and Treatment(IWGMRT)[J]. Leukemia Res, 2007, 31(6): 737-740.
- 39. Girodon F, Bonicelli G, Schaeffer C, et al. Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: population-based study [J]. Haematologica, 2009, 94(6): 865-869.
- 40. Dingli D, Grand FH, Mahaffey V, et al. Der(6)t(1;6)(q21-23; p21.3): a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia [J]. Br J Haematol, 2005, 130(2): 229-232.
- 41. 赖永榕. 真性红细胞增多症的诊断和治疗[J]. 内科危急重症杂志, 2009, 15(2): 66-73.
- 42. 洪鸣, 徐卫, 李建勇. 原发性骨髓纤维化的诊断和鉴别诊断[J]. 内科危急重症杂志, 2009(15): 68-70.
- 43. Verstovsek S, Pardanani AD, Shah NP, et al. A phaseⅠstduy of XL019, a selective JAK2inhibitor, in patients with primary myelofibrosis and post-polycythemia vera/essential thrombocythemia myelofibrosis[J]. Blood, 2007, 110.
- 44. Levine R, Heaney M. New advances in the pathogenesis and therapy of essential thrombocythemia[J]. Hematology, 2008, 207(1): 76-82.