Integrated genomic analyses identify high-risk factors and actionable targets in T-cell acute lymphoblastic leukemia.

IF 1.5 Q3 HEMATOLOGY
血液科学(英文) Pub Date : 2022-02-04 eCollection Date: 2022-01-01 DOI:10.1097/BS9.0000000000000102
Haichuan Zhu, Bingjie Dong, Yingchi Zhang, Mei Wang, Jianan Rao, Bowen Cui, Yu Liu, Qian Jiang, Weitao Wang, Lu Yang, Anqi Yu, Zongru Li, Chao Liu, Leping Zhang, Xiaojun Huang, Xiaofan Zhu, Hong Wu
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引用次数: 0

Abstract

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy often associated with poor outcomes. To identify high-risk factors and potential actionable targets for T-ALL, we perform integrated genomic and transcriptomic analyses on samples from 165 Chinese pediatric and adult T-ALL patients, of whom 85% have outcome information. The genomic mutation landscape of this Chinese cohort is very similar to the Western cohort published previously, except that the rate of NOTCH1 mutations is significant lower in the Chinese T-ALL patients. Among 47 recurrently mutated genes in 7 functional categories, we identify RAS pathway and PTEN mutations as poor survival factors for non-TAL and TAL subtypes, respectively. Mutations in the PI3K pathway are mutually exclusive with mutations in the RAS and NOTCH1 pathways as well as transcription factors. Further analysis demonstrates that approximately 43% of the high-risk patients harbor at least one potential actionable alteration identified in this study, and T-ALLs with RAS pathway mutations are hypersensitive to MEKi in vitro and in vivo. Thus, our integrated genomic analyses not only systematically identify high-risk factors but suggest that these high-risk factors are promising targets for T-ALL therapies.

综合基因组分析确定T细胞急性淋巴细胞白血病的高危因素和可操作的靶点
摘要T细胞急性淋巴细胞白血病(T-ALL)是一种侵袭性血液系统恶性肿瘤,通常预后不佳。为了确定T-ALL的高危因素和潜在的可操作靶点,我们对165名中国儿童和成人T-ALL患者的样本进行了综合基因组和转录组分析,其中85%的患者有结果信息。该中国队列的基因组突变情况与之前发表的西方队列非常相似,只是中国T-ALL患者的NOTCH1突变率显著较低。在7个功能类别的47个复发突变基因中,我们确定RAS途径和PTEN突变分别是非TAL和TAL亚型的不良生存因素。PI3K途径的突变与RAS和NOTCH1途径以及转录因子的突变相互排斥。进一步的分析表明,大约43%的高危患者至少有一种在本研究中确定的潜在可操作的改变,并且具有RAS途径突变的T-ALL在体外和体内对MEKi过敏。因此,我们的综合基因组分析不仅系统地确定了高危因素,而且表明这些高危因素是T-ALL治疗的有希望的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
1.70
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0.00%
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10 weeks
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