Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia
Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia
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DOI：
10.1182/blood-2007-07-103960
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Issa, Jean-Pierre J.
中科院分区：
文献类型：
--
作者：
Oki, Yasuhiro;Jelinek, Jaroslav;Issa, Jean-Pierre J.
地西他滨在慢性粒单核细胞白血病中的作用机制仍不完全清楚。我们通过焦磷酸测序定量监测突变等位基因，研究了地西他滨治疗（100 mg/m2/疗程，每4周一次）期间肿瘤细胞清除的动力学。首先对慢性粒单核细胞白血病患者进行JAK 2和NPM 1突变筛查，确定了3例突变患者。处理后跟踪单核细胞DNA中的突变等位基因百分比，沿着LINE 1和10个其他基因的甲基化。尽管诱导了低甲基化，但在第一个周期后突变等位基因的清除是适度的。在2至4个周期后观察到延迟的实质性清除，这与临床应答相关。2例患者突变等位基因完全消失，临床缓解持续。另1例患者在临床缓解时检测到突变等位基因，缓解持续8个月。我们的数据表明，地西他滨的作用机制主要是非细胞毒性的，导致肿瘤克隆和/或正常细胞的生物学改变。该试验在www.ClinicalTrials.gov上注册为#NCT00067808。
Decitabine's mechanism of action in chronic myelomonocytic leukemia remains incompletely understood. We studied the dynamics of neoplastic cell clearance during decitabine treatment (100 mg/m(2) per course every 4 weeks) using quantitative monitoring of mutant alleles by pyrosequencing. Patients with chronic myelomonocytic leukemia were first screened for JAK2 and NPM1 mutations, and 3 patients with mutations were identified. Mutant allele percentages in mononuclear cell DNA were followed after treatment, along with methylation of LINE1 and 10 other genes. The clearance of mutant alleles was modest after the first cycle, despite induction of hypo-methylation. Delayed substantial clearance was observed after 2 to 4 cycles that correlated with clinical response. Two patients had complete disappearance of mutant alleles and sustained clinical remissions. In another patient, mutant allele was detectable at clinical remission, which lasted for 8 months. Our data suggest a predominantly noncytotoxic mechanism of action for decitabine, leading to altered biology of the neoplastic clone and/or normal cells. This trial was registered at www.ClinicalTrials.gov as #NCT00067808.