DNA甲基化靶向药物在急性髓系白血病中的应用

常乃柏

doi:10.3969/j.issn.1000-8179.2017.02.268

DNA甲基化靶向药物在急性髓系白血病中的应用

doi: 10.3969/j.issn.1000-8179.2017.02.268

常乃柏^,

北京医院血液科，国家老年医学研究中心（北京市 100730）

基金项目:

本文课题受首都医学发展科研专项 2016-1-4052

详细信息

通讯作者:
常乃柏，教授，主任医师，硕士研究生导师。现任中国药理学会化疗药理专业委员会委。兼任《白血病·淋巴瘤》编委，《PLoS ONE》、《中国医学科学院学报》、《中华临床医师杂志》等期刊审稿人。研究方向主要为老年血液肿瘤的治疗以及髓系肿瘤相关基因表达和DNA甲基化研究。先后承担国家及省部级课题8项、局级课题2项，参编专著3部、研究生教材2部，在国内外期刊发表论文70余篇。changnaibai@sohu.com

计量
- 文章访问数: 63
- HTML全文浏览量: 3
- PDF下载量: 6
- 被引次数: 0
出版历程
- 收稿日期: 2016-11-03
- 修回日期: 2016-12-14
- 刊出日期: 2017-01-30

Targeting DNA methylation in the treatment of acute myeloid leukemia

CHANG Naibai^,

Department of Hematology, Beijing Hospital, The National Center of Gerontology, Beijing 100730, China

Funds:

This work was supported by the Project for the Advances of the Capital Medical Science 2016-1-4052

More Information

Corresponding author: Naibai CHANG; E-mail: changnaibai@sohu.com

摘要

摘要: DNA甲基化和组蛋白甲基化是急性髓系白血病（acute myeloid leukemia，AML）表观遗传学调控的常见模式，针对甲基化过程的靶向治疗包括DNA甲基转移酶抑制剂、甲基化调节蛋白抑制剂及组蛋白甲基化调控蛋白抑制剂，其中DNA甲基转移酶（DNA methyltransferase，DNMT）抑制剂阿扎胞苷、地西他滨已上市进入临床，针对甲基化调节蛋白IDH1/2抑制剂也已进入Ⅱ期临床研究。此外，针对组蛋白甲基化调控蛋白EZH2、LSD1抑制剂也显示出良好体外抗白血病活性，部分已进入Ⅰ期临床研究，为AML的治疗提供新的选择。
- 急性髓系白血病 /
- DNA甲基化 /
- 组蛋白甲基化 /
- 治疗
Abstract: DNA and histone lysine methylations are the main epigenetic modulatory elements in the development and progression of acute myeloid leukemia. Methylation-targeted therapy includes DNA methyltransferase, methylation modulatory protein, and histonelysine methylation inhibitors. Approved DNA methyltransferase inhibitor (demethylating agent) includes azacytidine and dicitabine, which have been used as antileukemic drug clinically. IDH1/2 inhibitor also showed effective and well tolerated in leukemic patients in phase Ⅱ clinical study. EZH2 inhibitor and LSD1 inhibitor have completed in vitro study and entered clinical trial. Targeting DNA and histone lysine methylations is an alternative approach for leukemia treatment.
- acute myeloid leukemia /
- DNA methylation /
- histone lysine methylation /
- therapy

HTML全文

参考文献(25)

[1]	Figueroa ME, Lugthart S, Li Y, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia[J]. Cancer Cell, 2010, 17(1):13-27. doi: 10.1016/j.ccr.2009.11.020
[2]	Kohli RM, Zhang Y. TET enzyme, TDG and dynamics of DNA demethylation[J]. Nature, 2013, 502(7432):472-479.
[3]	常乃柏.急性髓系白血病DNA甲基化及治疗进展[J].中华临床医师杂志(电子版), 2013, 7(12):5504-5506. http://www.cnki.com.cn/Article/CJFDTOTAL-ZLYD201312073.htm Chang NB. Recent advances in DNA methylation and treatment in patients with acute myeloidleukemia[J]. Chin J Clinicians (Electronic edition), 2013, 7(12):5504-5506. http://www.cnki.com.cn/Article/CJFDTOTAL-ZLYD201312073.htm
[4]	Cashen AF, Schiller GJ, O'Donnell MR, et al. Multiceter, phase Ⅱ study of decitabine for the first line treatment of older patients with acute myeloid leukemia[J]. J Clin Oncol, 2010, 28(4):556-561. doi: 10.1200/JCO.2009.23.9178
[5]	Kantarjian HM, Thomas XG, Dmoszyska A, et al. Multicenter, randomized, open-lebel, phase Ⅲ trial of decitabine versus patients choice, with physician advice, of either supportive care or low dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia[J]. J Clin Oncol, 2012, 30(21):2670-2677. doi: 10.1200/JCO.2011.38.9429
[6]	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):7473-7479. doi: 10.1073/pnas.1002650107
[7]	Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia[J]. J Clin Oncol, 2010, 28(4):562-569. doi: 10.1200/JCO.2009.23.8329
[8]	Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs. conventional care regimens in older patients with newly diagnosed AML with >30% blasts[J]. Blood, 2015, 126(3):291-299. doi: 10.1182/blood-2015-01-621664
[9]	Onda K, Suzuki R, Tanaka S, et al. Decitabine, a DNA methyltransferase inhabitor, induces P-glycoprotein mRNA and protein expressions and increases drug sensitivity in drug-resistance MOLT4 and Jurkat cell lines [J]. Anticancer Res, 2012, 32(10):4439-4444.
[10]	Jerez A, Sugimoto Y, Makeshima H, et al. Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis[J]. Blood, 2012, 119(25):6109-6117. doi: 10.1182/blood-2011-12-397620
[11]	Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA methylations is a dominant mechanism in MDS progression to AML[J]. Blood, 2009, 113 (6):1315-1325. doi: 10.1182/blood-2008-06-163246
[12]	Cabrero M, Jabbour E, Ravandi F, et al. Discontinuation of hypomethylating agent therapy in patients with myelodisplastic syndromes or acute myelogenous leukemia in complete remission or partial response: retrospective analysis of survival after long-term follow-up[J]. Leuk Res, 2015, 39(5):520-524. doi: 10.1016/j.leukres.2015.03.006
[13]	Ørskov AD, Treppendahl MB, Skovbo A, et al. Hypomethylation and upregulation of PD-1 in T cells by azacitidine in MDS/AML patients: a rationale for combined targeting of PD-1 and DNA methylation[J]. Oncotarget, 2015, 6(11):9612-9626. doi: 10.18632/oncotarget
[14]	Yun S, Vincelette ND, Abraham I, et al. Targeting epigenetic pathways in acute myeloid leukemia and myelodysplastic syndrome: a systemic review of hypomethylaing agents trials[J]. Clin Epigenetics, 2016, 8(3): 68-77. doi: 10.1056/NEJM199909303411407?query=prevarrow
[15]	Scandura JM, Roboz GJ, Moh M, et al. Phase Ⅰ study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML[J]. Blood, 2011, 118(6):1472-1480. doi: 10.1182/blood-2010-11-320093
[16]	Dinardo CD, Patel KP, Garcia-Manero G, et al. Lack of association of IDH1, IDH2, and DNMT3A mutations with outcomes in older patients with AML treated with hypomethylating agents[J]. Leuk Lymphoma, 2014, 55(8):1925-1929. doi: 10.3109/10428194.2013.855309
[17]	Metzeler KH, Walker A, Geyer S, et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia[J]. Leukemia, 2012, 26(5):1106-1107. doi: 10.1038/leu.2011.342
[18]	Stein EM, Altman JK, Collins R, et al. AG-221, an oral, selective, first-inclass, potent inhibitor of the IDH2 mutant metabolic enzyme, induces durable remissions in a phase Ⅰ study in patients with IDH2 mutation positive advanced hematologic malignancies[J]. Blood, 2014, 124(21): 115.
[19]	Stein EM, DiNardo C, Altman JK, et al. Safety and efficacy of AG-221, a potent inhibitor of mutant IDH2 that promote differentiation of myeloid cells in patients with advanced hematological malignancies: results of a phase Ⅰ/Ⅱ trial[J]. Blood, 2015, 126(21):323.
[20]	DiNardo C, de Botton S, Pollyea DA, et al. Molecular profile and relationship with clinical response in patients with IDH1 mutation-positive hematologic malignancies receiving AG-120, a first-in-class potent inhibitor of mutant IDH1, in addition to data from the completed dose escalation portion of the phase 1 study[J]. Blood, 2015, 126(21):1306.
[21]	Barski A, Cuddapah S, Cui K, et al. High-resolution profiling of histone methylation in the human genome[J]. Cell, 2007, 129(4):823-837. doi: 10.1016/j.cell.2007.05.009
[22]	Girard N, Bazille C, Lhuissier E, et al. 3-Deazaneplanocin A (DZNep), an inhibitor of the histone methyltransferase EZH2, induces apoptosis and reduces cell migration in chondrosarcoma cells[J]. PLoS ONE, 2014, 9: e98176. doi: 10.1371/journal.pone.0098176
[23]	Bernt KM, Zhu N, Sinha AU, et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L[J]. Cancer Cell, 2011, 20(1):66-78. doi: 10.1016/j.ccr.2011.06.010
[24]	Stein EM, Garcia-Manero G, Rizzieri DA, et al. The DOT1L inhibitor EPZ-5676: safety and activity in relapsed/refractory patients with MLLrearranged leukemia[J]. Blood, 2014, 124(21):387. http://www.bloodjournal.org/content/124/21/387?sso-checked=true
[25]	Harris WJ, Huang X, Lynch JT, et al. Pharmacological inhibition or genetic knockdown of Kdm1a (Lsd1 or Aof2) induces differentiation of MLL acute myeloid leukemia stem cells[J]. Blood, 2011, 118(1):28-29. doi: 10.1182/blood-2010-10-313908

施引文献

资源附件(0)

访问统计

点击查看大图

计量

文章访问数: 63
HTML全文浏览量: 3
PDF下载量: 6
被引次数: 0

DNA甲基化靶向药物在急性髓系白血病中的应用

doi: 10.3969/j.issn.1000-8179.2017.02.268

计量

出版历程

Targeting DNA methylation in the treatment of acute myeloid leukemia

Corresponding author: Naibai CHANG; E-mail: changnaibai@sohu.com

计量

出版历程

目录