• 成都市第三人民醫(yī)院　重慶醫(yī)科大學(xué)成都第二臨床學(xué)院血液科（成都，610031）;

【摘要】　 近年來(lái)大量的研究對(duì)骨髓增殖性疾病發(fā)病機(jī)制有了更進(jìn)一步的認(rèn)識(shí)。其中最重要的發(fā)現(xiàn)是出現(xiàn)在絕大多數(shù)陣型紅細(xì)胞增多癥和一半左右原發(fā)性血小板增多癥及骨髓纖維化的JAK2 V617F突變，能使細(xì)胞增殖活性明顯增強(qiáng)，并引起細(xì)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(duì)慢性粒細(xì)胞白血病的急變機(jī)制及對(duì)伊馬替尼的耐藥機(jī)制也有了更多的認(rèn)識(shí)。這些新的發(fā)現(xiàn)影響了慢性骨髓增殖性腫瘤的診斷標(biāo)準(zhǔn)與流程，并對(duì)其治療提供了新的靶點(diǎn)。

引用本文： 郭海鷹. 骨髓增殖性腫瘤發(fā)病機(jī)制的研究進(jìn)展及臨床應(yīng)用. 華西醫(yī)學(xué), 2011, 26(12): 1798-1804. doi: 復(fù)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(rèn)知和治療[J]. 國(guó)際輸血及血液學(xué)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(dá)譜研究[J]. 中國(guó)試驗(yàn)血液學(xué)雜志, 2010, 18(3): 575-578.
16. 　陳穎, 戴敏, 馬萍. 慢性粒細(xì)胞白血病發(fā)病機(jī)制的研究進(jìn)展[J]. 現(xiàn)代臨床醫(yī)學(xué), 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(xì)胞白血病353例的染色體核型分析[J]. 中華內(nèi)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(xiàn)代腫瘤醫(yī)學(xué), 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(xì)胞增多癥的診斷和治療[J]. 內(nèi)科危急重癥雜志, 2009, 15(2): 66-73.
42. 　洪鳴, 徐衛(wèi), 李建勇. 原發(fā)性骨髓纖維化的診斷和鑒別診斷[J]. 內(nèi)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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 12. 　吳迪炯, 孫潔, 周郁鴻, 等. 骨髓增殖性疾病的認(rèn)知和治療[J]. 國(guó)際輸血及血液學(xué)雜志, 2010, 33(3): 276-279.
  13. 13. 　Cortes JE, Talpaz M, Kantarjian H. Chronic myelogenous leukemia: a review [J]. Am J Med, 1996, 100(5): 555-570.
  14. 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. 15. 　高素君, 朱迅, 姚程, 等. 慢性髓系白血病不同病期基因表達(dá)譜研究[J]. 中國(guó)試驗(yàn)血液學(xué)雜志, 2010, 18(3): 575-578.
  16. 16. 　陳穎, 戴敏, 馬萍. 慢性粒細(xì)胞白血病發(fā)病機(jī)制的研究進(jìn)展[J]. 現(xiàn)代臨床醫(yī)學(xué), 2009(35): 163-164.
  17. 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. 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. 19. 　陳志妹, 金潔, 樓基余, 等. 慢性粒細(xì)胞白血病353例的染色體核型分析[J]. 中華內(nèi)科雜志, 2002, 41(6): 414.
  20. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 31. 　于亞平. 骨髓增生腫瘤WHO2008修訂分類及臨床診斷方法[J]. 現(xiàn)代腫瘤醫(yī)學(xué), 2009(17): 743-747.
  32. 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. 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. 34. 　Anthony JB, Heike LP. Chromosome abnormalities and molecular markers in myeloprolificative disorders [J]. Semin Hematol, 2005, 42(4): 196-205.
  35. 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. 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. 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. 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. 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. 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. 41. 　賴永榕. 真性紅細(xì)胞增多癥的診斷和治療[J]. 內(nèi)科危急重癥雜志, 2009, 15(2): 66-73.
  42. 42. 　洪鳴, 徐衛(wèi), 李建勇. 原發(fā)性骨髓纖維化的診斷和鑒別診斷[J]. 內(nèi)科危急重癥雜志, 2009(15): 68-70.
  43. 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. 44. 　Levine R, Heaney M. New advances in the pathogenesis and therapy of essential thrombocythemia[J]. Hematology, 2008, 207(1): 76-82.