Zhan Di, Zhang Yingchi, Xiao Peifang, Zheng Xinchang, Ruan Min, Zhang Jingliao, Chen Aili, Zou Yao, Chen Yumei, Huang Gang, Hu Shaoyan, Wang Qian-Fei, Zhu Xiaofan
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Leuk Res. 2018 Feb;65:20-24. doi: 10.1016/j.leukres.2017.12.001. Epub 2017 Dec 8.
Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo-resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C, SRIT6, CHD4, and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP, TCF3, SS18, and BCL10, may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML.
小儿急性髓系白血病（AML）中化疗耐药的基因组改变仍未得到充分表征。在本研究中，我们使用全外显子组测序来鉴定44例小儿AML患者中与化疗耐药相关的基因突变。我们在小儿AML患者中发现了涉及表观遗传调节因子（如KDM5C、SRIT6、CHD4和PRPF6）的先前未报道的突变。尽管在一般小儿AML中发生率较低，但涉及包括剪接因子在内的表观遗传调节因子的突变在原发性化疗耐药AML患者中作为一个群体共同富集。此外，对继发性化疗耐药AML患者的克隆进化分析表明，诊断时的优势克隆可以在几个强化化疗疗程中存活下来。而MVP、TCF3、SS18和BCL10等基因中新突变的获得可能导致复发时的化疗耐药。这些结果为小儿AML治疗失败的遗传基础提供了新的见解。
