CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine
CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine
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DOI：
10.1038/sj.leu.2404796
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发表时间：
2007-09-01
期刊：
影响因子：
11.4
通讯作者：
Mufti, G. J.
中科院分区：
文献类型：
--
作者：
Raj, K.;John, A.;Mufti, G. J.
5-氮杂胞苷是一种DNA甲基转移酶抑制剂，对骨髓增生异常综合征（MDS）患者有效。对5-氮杂胞苷的反应是通过关键基因的去甲基化还是通过细胞毒性实现的尚不清楚。34例MDS或急性髓性白血病（AML）患者接受5-氮杂胞苷治疗，7例达到完全缓解（CR）（21%），6例血液学改善。在血液学改善（HI）时，所有6例患者的骨髓（BM）原始细胞均低于5%（2例患者先前存在难治性贫血（RA），4例患者存在难治性贫血伴原始细胞过多（RAEB））。另一名RAEB患者的原始细胞减少至小于5%，无HI。7例完全缓解者中有5例（71%）有7号染色体异常。BM CR预测总生存期（OS）更长（中位23个月vs 9个月，P 0.015）。CDKN 2B（p15（INK 4 b））启动子的亚硫酸氢盐基因组测序（BGS）显示，在14/ 17（82%）分析的患者中，治疗前甲基化水平较低，异质性（平均12.2%）。应答者的基线甲基化水平较低（9.8% vs 16.2%，无应答者P 0.07）。在424%甲基化的患者中没有观察到反应，其中p15 INK 4 b mRNA不表达。5-在8/ 17例（47%）患者中，氮杂胞苷使CDKN 2B甲基化平均降低6.8%，但这与缓解无关。在75 mg/m2时，细胞死亡（BM细胞构成减少（P 0.001）和凋亡增加（P 0.02））而不是CDKN 2B的去甲基化与缓解相关。424%甲基化的患者可能受益于替代给药或联合策略。
5- Azacytidine, a DNA methyl transferase inhibitor, is effective in patients with myelodysplastic syndromes ( MDS). Whether responses to 5- Azacytidine are achieved by demethylation of key genes or by cytotoxicity is unclear. Of 34 patients with MDS or acute myeloid leukaemia ( AML) treated with 5- Azacytidine, 7 achieved complete remissions ( CR) ( 21%) and 6 achieved haematological improvement. All six had less than 5% bone marrow ( BM) blasts at the time of haematological improvements ( HI) ( 2 had pre- existing refractory anaemia ( RA), 4 had refractory anaemia with excess blasts ( RAEB)). A further patient with RAEB had blast reduction to less than 5% without HI. Five of the seven ( 71%) complete responders had chromosome 7 abnormalities. BM CR predicted longer overall survival ( OS) ( median 23 versus 9 months, P 0.015). Bisulphite genomic sequencing ( BGS) of the CDKN2B ( p15 (INK4b)) promoter showed low level, heterogeneous pretreatment methylation ( mean 12.2%) in 14/ 17 ( 82%) patients analysed. Lower baseline methylation occurred in responders ( 9.8% versus 16.2% in non- responders P 0.07). No response was seen in patients with 424% methylation, in whom p15 INK4b mRNA was not expressed. 5- Azacytidine reduced CDKN2B methylation by mean 6.8% in 8/ 17 ( 47%) patients, but this did not correlate with response. At 75mg/ m 2, cell death ( reduced BM cellularity ( P 0.001) and increased apoptosis ( P 0.02)) rather than demethylation of CDKN2B correlates with response. Patients with 424% methylation may benefit from alternative dosing or combination strategies.