骨髓增殖性腫瘤發病機制的研究進展及臨床應用_《華西醫學》

作者：

郭海鷹

成都市第三人民醫院　重慶醫科大學成都第二臨床學院血液科（成都，610031）;

關鍵詞：

骨髓增殖性腫瘤發病機制診斷標準及流程

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【摘要】　近年來大量的研究對骨髓增殖性疾病發病機制有了更進一步的認識。其中最重要的發現是出現在絕大多數陣型紅細胞增多癥和一半左右原發性血小板增多癥及骨髓纖維化的JAK2 V617F突變，能使細胞增殖活性明顯增強，并引起細胞的增殖和凋亡抑制。其他的突變包括JAK2外顯子12突變、MPL突變等。對慢性粒細胞白血病的急變機制及對伊馬替尼的耐藥機制也有了更多的認識。這些新的發現影響了慢性骨髓增殖性腫瘤的診斷標準與流程，并對其治療提供了新的靶點。

引用本文： 郭海鷹. 骨髓增殖性腫瘤發病機制的研究進展及臨床應用. 華西醫學, 2011, 26(12): 1798-1804. doi: 復制

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.	吳迪炯, 孫潔, 周郁鴻, 等. 骨髓增殖性疾病的認知和治療[J]. 國際輸血及血液學雜志, 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達譜研究[J]. 中國試驗血液學雜志, 2010, 18(3): 575-578.
16.	陳穎, 戴敏, 馬萍. 慢性粒細胞白血病發病機制的研究進展[J]. 現代臨床醫學, 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.	陳志妹, 金潔, 樓基余, 等. 慢性粒細胞白血病353例的染色體核型分析[J]. 中華內科雜志, 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.	于亞平. 骨髓增生腫瘤WHO2008修訂分類及臨床診斷方法[J]. 現代腫瘤醫學, 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.	賴永榕. 真性紅細胞增多癥的診斷和治療[J]. 內科危急重癥雜志, 2009, 15(2): 66-73.
42.	洪鳴, 徐衛, 李建勇. 原發性骨髓纖維化的診斷和鑒別診斷[J]. 內科危急重癥雜志, 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. 　吳迪炯, 孫潔, 周郁鴻, 等. 骨髓增殖性疾病的認知和治療[J]. 國際輸血及血液學雜志, 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達譜研究[J]. 中國試驗血液學雜志, 2010, 18(3): 575-578.
16. 　陳穎, 戴敏, 馬萍. 慢性粒細胞白血病發病機制的研究進展[J]. 現代臨床醫學, 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. 　陳志妹, 金潔, 樓基余, 等. 慢性粒細胞白血病353例的染色體核型分析[J]. 中華內科雜志, 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. 　于亞平. 骨髓增生腫瘤WHO2008修訂分類及臨床診斷方法[J]. 現代腫瘤醫學, 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. 　賴永榕. 真性紅細胞增多癥的診斷和治療[J]. 內科危急重癥雜志, 2009, 15(2): 66-73.
42. 　洪鳴, 徐衛, 李建勇. 原發性骨髓纖維化的診斷和鑒別診斷[J]. 內科危急重癥雜志, 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.

《華西醫學》

骨髓增殖性腫瘤發病機制的研究進展及臨床應用

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《華西醫學》

骨髓增殖性腫瘤發病機制的研究進展及臨床應用

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

Format

Content

摘要全文圖表視頻參考文獻施引文獻補充材料