• 四川大學(xué)華西醫(yī)院血液科及血液病研究所（成都，610041）;

骨髓增生異常綜合征（MDS）是一種起源于造血干細(xì)胞的克隆性疾病，疾病臨床表現(xiàn)呈異質(zhì)性，多數(shù)患者最終轉(zhuǎn)化為急性髓細(xì)胞性白血病。近年來發(fā)現(xiàn)DNA甲基化異常與MDS的嚴(yán)重程度及預(yù)后有關(guān)，去甲基化治療作為一種新的方法引入到MDS的治療中。現(xiàn)將指導(dǎo)MDS患者臨床合理使用去甲基化藥物的生物學(xué)指標(biāo)進(jìn)行綜述。

引用本文： 羅朝蕊,劉霆. 骨髓增生異常綜合征去甲基化藥物臨床反應(yīng)的生物學(xué)標(biāo)志研究進(jìn)展. 華西醫(yī)學(xué), 2012, 27(5): 779-782. doi: 復(fù)制

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1. 　王吉耀, 廖二元, 胡品津. 內(nèi)科學(xué)[M]. 北京: 人民衛(wèi)生出版社, 2005: 740.
2. 　Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase Ⅲ randomized study[J]. Cancer, 2006, 106(8): 1794-1803.
3. 　Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia[J]. Blood, 2007, 109(1): 52-57.
4. 　Sekeres MA, Steensma DP. Defining prior therapy in myelodysplastic syndromes and criteria for relapsed and refractory disease: implications for clinical trial design and enrollment[J]. Blood, 2009, 114(13): 2575-2580.
5. 　Lubbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate-or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phaseⅢ study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study[J]. J Clin Oncol, 2011, 29(15): 1987-1996.
6. 　Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes[J]. Cancer, 2011, 117(12): 2697-2702.
7. 　邊祥海. 地西他濱在骨髓增生異常綜合征治療中的應(yīng)用[J]. 國際輸血及血液學(xué)雜志, 2010, 33(4): 374-376.
8. 　邵宗鴻, 張薇. 骨髓增生異常綜合征去甲基化治療進(jìn)展[J]. 臨床血液學(xué)雜志, 2011, 24(3): 259-261.
9. 　Jones PA, Baylin SB. The fundamental role of epigenetic events in Cancer[J]. Nat Rev Genet, 2002, 3(6): 415-428.
10. 　Quesnel B. Methylation and myelodysplastic syndromes: when and where?[J]. Leuk Res, 2006, 30(11): 1327-1329.
11. 　Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML[J]. Blood, 2009, 113(6): 1315-1325.
12. 　Figueroa ME, Skrabanek L, Li Y, et al. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation[J]. Blood, 2009, 114(16): 3448-3458.
13. 　Musolino G, Antonio ES, Penna G, et al. Epigenetic therapy in myelodysplastic syndromes[J]. Eur J Haematol, 2009, 84(6): 463-473.
14. 　Solomon PR, Munirajan AK, Tsuchida N, et al. Promoter hypermethylation analysis in myelodysplastic syndromes: diagnostic & prognostic implication[J]. Indian J Med Res, 2008, 127(1): 52-57.
15. 　葉雪石, 劉霆, 崔旭, 等. 骨髓增生異常綜合征P15INK4B基因甲基化及藥物去甲基化作用[J]. 四川大學(xué)學(xué)報(bào)(醫(yī)學(xué)版), 2007, 38(1): 57-59.
16. 　Aggerholm A, Holm MS, Guldberg P, et al. Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients[J]. Eur J Haematol, 2006, 76(1): 23-32.
17. 　Quesnel B, Guillerm G, Vereecque R, et al. Methylation of the p15 (INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression[J]. Blood, 1998, 91(8): 2985-2990.
18. 　Kim M, Oh B, Kim SY, et al. p15INK4b methylation correlates with thrombocytopenia, blast percentage, and survival in myelodysplastic syndromes in a dose dependent manner: quantitation using pyrosequencing study[J]. Leuk Res, 2010, 34(6): 718-722.
19. 　Gore SD, Baylin S, Sugar E, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms[J]. Cancer Res, 2006, 66(12): 6361-6369.
20. 　Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2’-deoxycytidine (decitabine) treatment[J]. Blood, 2002, 100(8): 2957-2964.
21. 　Raj K, John A, Ho A, et al. CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine[J]. Leukemia, 2007, 21(9): 1937-1944.
22. 　Yang AS, Doshi KD, Choi SW, et al. DNA methylation changes after 5-aza-2’-deoxycytidine therapy in patients with leukemia[J]. Cancer Res, 2006, 66(10): 5495-5503.
23. 　Fandy TE, Herman JG, Kerns P, et al. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies[J]. Blood, 2009, 114(13): 2764-2773.
24. 　Issa JP, Garcia-Manero G, Giles FJ, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2’-deoxycytidine (decitabine) in hematopoietic malignancies[J]. Blood, 2004, 103(5): 1635-1640.
25. 　Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2’-deoxycytidine with valproic acid in patients with leukemia[J]. Blood, 2006, 108(10): 3271-3279.
26. 　Stresemann C, Bokelmann I, Mahlknecht U, et al. Azacytidine causes complex DNA methylation responses in myeloid leukemia[J]. Mol Cancer Ther, 2008, 7(9): 2998-3005.
27. 　姚冬明, 錢軍, 許文榮, 等. 骨髓增生異常綜合征患者FHIT基因啟動(dòng)子甲基化改變[J]. 中華醫(yī)學(xué)遺傳學(xué)雜志, 2008, 25(1): 36-39.
28. 　Iwai M, Kiyoi H, Ozeki K, et al. Expression and methylation status of the FHIT gene in acute myeloid leukemia and myelodysplastic syndrome[J]. Leukemia, 2005, 19(8): 1367-1375.
29. 　Voso MT, Scardocci A, Guidi F, et al. Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes[J]. Blood, 2004, 103(2): 698-700.
30. 　Römermann D, Hasemeier B, Metzig K, et al. Global increase in DNA methylation in patients with myelodysplastic syndrome[J]. Leukemia, 2008, 22(10): 1954-1956.
31. 　Martin MG, Walgren RA, Procknow E, et al. A phaseⅡ study of 5-day intravenous azacitidine in patients with myelodysplastic syndromes[J]. Am J Hematol, 2009, 84(9): 560-564.
32. 　Ueki T, Toyota M, Sohn T, et al. Hypermethylation of multiple genes in pancreatic adenocarcinoma[J]. Cancer Res, 2000, 60(7): 1835-1839.
33. 　Shen L, Ahuja N, Shen Y, et al. DNA methylation and environmental exposures in human hepatocellular carcinoma[J]. J Natl Cancer Inst, 2002, 94(10): 755-761.
34. 　Shen L, Kantarjian H, Guo Y, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes[J]. J Clin Oncol, 2010, 28(4): 605-613.
35. 　Delhomeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers[J]. N Engl J Med, 2009, 360(22): 2289-2301.
36. 　Langemeijer SM, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes[J]. Nat Genet, 2009, 41(7): 838-842.
37. 　Kosmider O, Gelsi-Boyer V, Cheok M, et al. TET2 mutation is an Independent favorable prognostic factor in myelodysplastic syndromes (MDSs)[J]. Blood, 2009, 114(15): 3285-3291.
38. 　Itzykson R, Kosmider O, Cluzeau T, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias[J]. Leukemia, 2011, 25(7): 1147-1152.
39. 　Ito S, Shen L, Dai Q, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine[J]. Science, 2011, 333(6047): 1300-1303.
40. 　Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2[J]. Nature, 2010, 468(7325): 839-843.
41. 　Garzon R, Liu S, Fabbri M, et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1[J]. Blood, 2009, 113(25): 6411-6418.
42. 　Xiong Y, Li Z, Ji M, et al. MIR29B regulates expression of MLLT11 (AF1Q), an MLL fusion partner, and low MIR29B expression associates with adverse cytogenetics and poor overall survival in AML[J]. Br J Haematol, 2011, 153(6): 753-757.
43. 　Blum W, Garzon R, Klisovic RB, et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine[J]. Proc Natl Acad Sci USA, 2010, 107(16): 7473-7478.
  1. 1. 　王吉耀, 廖二元, 胡品津. 內(nèi)科學(xué)[M]. 北京: 人民衛(wèi)生出版社, 2005: 740.
  2. 2. 　Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase Ⅲ randomized study[J]. Cancer, 2006, 106(8): 1794-1803.
  3. 3. 　Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia[J]. Blood, 2007, 109(1): 52-57.
  4. 4. 　Sekeres MA, Steensma DP. Defining prior therapy in myelodysplastic syndromes and criteria for relapsed and refractory disease: implications for clinical trial design and enrollment[J]. Blood, 2009, 114(13): 2575-2580.
  5. 5. 　Lubbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate-or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phaseⅢ study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study[J]. J Clin Oncol, 2011, 29(15): 1987-1996.
  6. 6. 　Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes[J]. Cancer, 2011, 117(12): 2697-2702.
  7. 7. 　邊祥海. 地西他濱在骨髓增生異常綜合征治療中的應(yīng)用[J]. 國際輸血及血液學(xué)雜志, 2010, 33(4): 374-376.
  8. 8. 　邵宗鴻, 張薇. 骨髓增生異常綜合征去甲基化治療進(jìn)展[J]. 臨床血液學(xué)雜志, 2011, 24(3): 259-261.
  9. 9. 　Jones PA, Baylin SB. The fundamental role of epigenetic events in Cancer[J]. Nat Rev Genet, 2002, 3(6): 415-428.
  10. 10. 　Quesnel B. Methylation and myelodysplastic syndromes: when and where?[J]. Leuk Res, 2006, 30(11): 1327-1329.
  11. 11. 　Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML[J]. Blood, 2009, 113(6): 1315-1325.
  12. 12. 　Figueroa ME, Skrabanek L, Li Y, et al. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation[J]. Blood, 2009, 114(16): 3448-3458.
  13. 13. 　Musolino G, Antonio ES, Penna G, et al. Epigenetic therapy in myelodysplastic syndromes[J]. Eur J Haematol, 2009, 84(6): 463-473.
  14. 14. 　Solomon PR, Munirajan AK, Tsuchida N, et al. Promoter hypermethylation analysis in myelodysplastic syndromes: diagnostic & prognostic implication[J]. Indian J Med Res, 2008, 127(1): 52-57.
  15. 15. 　葉雪石, 劉霆, 崔旭, 等. 骨髓增生異常綜合征P15INK4B基因甲基化及藥物去甲基化作用[J]. 四川大學(xué)學(xué)報(bào)(醫(yī)學(xué)版), 2007, 38(1): 57-59.
  16. 16. 　Aggerholm A, Holm MS, Guldberg P, et al. Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients[J]. Eur J Haematol, 2006, 76(1): 23-32.
  17. 17. 　Quesnel B, Guillerm G, Vereecque R, et al. Methylation of the p15 (INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression[J]. Blood, 1998, 91(8): 2985-2990.
  18. 18. 　Kim M, Oh B, Kim SY, et al. p15INK4b methylation correlates with thrombocytopenia, blast percentage, and survival in myelodysplastic syndromes in a dose dependent manner: quantitation using pyrosequencing study[J]. Leuk Res, 2010, 34(6): 718-722.
  19. 19. 　Gore SD, Baylin S, Sugar E, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms[J]. Cancer Res, 2006, 66(12): 6361-6369.
  20. 20. 　Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2’-deoxycytidine (decitabine) treatment[J]. Blood, 2002, 100(8): 2957-2964.
  21. 21. 　Raj K, John A, Ho A, et al. CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine[J]. Leukemia, 2007, 21(9): 1937-1944.
  22. 22. 　Yang AS, Doshi KD, Choi SW, et al. DNA methylation changes after 5-aza-2’-deoxycytidine therapy in patients with leukemia[J]. Cancer Res, 2006, 66(10): 5495-5503.
  23. 23. 　Fandy TE, Herman JG, Kerns P, et al. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies[J]. Blood, 2009, 114(13): 2764-2773.
  24. 24. 　Issa JP, Garcia-Manero G, Giles FJ, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2’-deoxycytidine (decitabine) in hematopoietic malignancies[J]. Blood, 2004, 103(5): 1635-1640.
  25. 25. 　Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2’-deoxycytidine with valproic acid in patients with leukemia[J]. Blood, 2006, 108(10): 3271-3279.
  26. 26. 　Stresemann C, Bokelmann I, Mahlknecht U, et al. Azacytidine causes complex DNA methylation responses in myeloid leukemia[J]. Mol Cancer Ther, 2008, 7(9): 2998-3005.
  27. 27. 　姚冬明, 錢軍, 許文榮, 等. 骨髓增生異常綜合征患者FHIT基因啟動(dòng)子甲基化改變[J]. 中華醫(yī)學(xué)遺傳學(xué)雜志, 2008, 25(1): 36-39.
  28. 28. 　Iwai M, Kiyoi H, Ozeki K, et al. Expression and methylation status of the FHIT gene in acute myeloid leukemia and myelodysplastic syndrome[J]. Leukemia, 2005, 19(8): 1367-1375.
  29. 29. 　Voso MT, Scardocci A, Guidi F, et al. Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes[J]. Blood, 2004, 103(2): 698-700.
  30. 30. 　Römermann D, Hasemeier B, Metzig K, et al. Global increase in DNA methylation in patients with myelodysplastic syndrome[J]. Leukemia, 2008, 22(10): 1954-1956.
  31. 31. 　Martin MG, Walgren RA, Procknow E, et al. A phaseⅡ study of 5-day intravenous azacitidine in patients with myelodysplastic syndromes[J]. Am J Hematol, 2009, 84(9): 560-564.
  32. 32. 　Ueki T, Toyota M, Sohn T, et al. Hypermethylation of multiple genes in pancreatic adenocarcinoma[J]. Cancer Res, 2000, 60(7): 1835-1839.
  33. 33. 　Shen L, Ahuja N, Shen Y, et al. DNA methylation and environmental exposures in human hepatocellular carcinoma[J]. J Natl Cancer Inst, 2002, 94(10): 755-761.
  34. 34. 　Shen L, Kantarjian H, Guo Y, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes[J]. J Clin Oncol, 2010, 28(4): 605-613.
  35. 35. 　Delhomeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers[J]. N Engl J Med, 2009, 360(22): 2289-2301.
  36. 36. 　Langemeijer SM, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes[J]. Nat Genet, 2009, 41(7): 838-842.
  37. 37. 　Kosmider O, Gelsi-Boyer V, Cheok M, et al. TET2 mutation is an Independent favorable prognostic factor in myelodysplastic syndromes (MDSs)[J]. Blood, 2009, 114(15): 3285-3291.
  38. 38. 　Itzykson R, Kosmider O, Cluzeau T, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias[J]. Leukemia, 2011, 25(7): 1147-1152.
  39. 39. 　Ito S, Shen L, Dai Q, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine[J]. Science, 2011, 333(6047): 1300-1303.
  40. 40. 　Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2[J]. Nature, 2010, 468(7325): 839-843.
  41. 41. 　Garzon R, Liu S, Fabbri M, et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1[J]. Blood, 2009, 113(25): 6411-6418.
  42. 42. 　Xiong Y, Li Z, Ji M, et al. MIR29B regulates expression of MLLT11 (AF1Q), an MLL fusion partner, and low MIR29B expression associates with adverse cytogenetics and poor overall survival in AML[J]. Br J Haematol, 2011, 153(6): 753-757.
  43. 43. 　Blum W, Garzon R, Klisovic RB, et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine[J]. Proc Natl Acad Sci USA, 2010, 107(16): 7473-7478.