文章：

新诊断的慢性髓性白血病中表观遗传调控因子频繁发生体细胞突变

Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia

原文发布日期：2017-04-28

DOI: 10.1038/bcj.2017.36

类型: Original Article

开放获取: 是

英文摘要：

Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1–17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ⩾6 showed higher rate of achieving major molecular response than those<6 (P=0.0381). Mutations in epigenetic regulator, ASXL1, TET2, TET3, KDM1A and MSH6 were found in 25% of patients. TET2 or TET3, AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1.

摘要翻译： 

尽管酪氨酸激酶抑制剂（TKI）显著改善了慢性髓系白血病（CML）的预后，但其根除CML的能力仍不确定，患者必须长期持续接受TKI治疗。本研究对参加JALSG CML212研究的24例新诊断慢性期CML患者进行全外显子测序以鉴定体细胞突变。除BCR-ABL1融合基因外，共发现191个体细胞突变（中位数8个，范围1-17）。年龄、血红蛋白浓度和白细胞计数与突变数量呈正相关。突变数≥6的患者获得主要分子学反应的比例高于<6者（P=0.0381）。25%的患者存在表观遗传调控因子ASXL1、TET2、TET3、KDM1A和MSH6突变，其中TET2、TET3、AKT1和RUNX1各有1例突变，3例患者发现ASXL1第12外显子突变。突变基因在细胞信号传导和细胞分裂通路中显著富集。此外，DNA拷贝数分析显示24例患者中有2例存在1p或3q染色体单亲二倍体，该异常在获得主要分子学反应后消失。这些突变除强驱动突变BCR-ABL1外，可能在CML发病机制中发挥重要作用。

原文链接：

Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia