Alternative polyadenylation dysregulation contributes to the differentiation block of acute myeloid leukemia.

基因敲除 生物 髓系白血病 非翻译区 癌症研究 髓样 下调和上调 聚腺苷酸 白血病 造血 CEBPA公司 骨髓 运行x1 信使核糖核酸 GATA1公司 细胞生物学
作者
Amanda G Davis,Daniel T Johnson,Dinghai Zheng,Ruijia Wang,Nathan D. Jayne,Mengdan Liu,Jihae Shin,Luyang Wang,Samuel A Stoner,Jie-Hua Zhou,Edward D. Ball,Bin Tian,Dong-Er Zhang
出处
期刊:Blood [American Society of Hematology]
卷期号:139 (3): 424-438 被引量:1
标识
DOI:10.1182/blood.2020005693
摘要

Posttranscriptional regulation has emerged as a driver for leukemia development and an avenue for therapeutic targeting. Among posttranscriptional processes, alternative polyadenylation (APA) is globally dysregulated across cancer types. However, limited studies have focused on the prevalence and role of APA in myeloid leukemia. Furthermore, it is poorly understood how altered poly(A) site usage of individual genes contributes to malignancy or whether targeting global APA patterns might alter oncogenic potential. In this study, we examined global APA dysregulation in patients with acute myeloid leukemia (AML) by performing 3' region extraction and deep sequencing (3'READS) on a subset of AML patient samples along with healthy hematopoietic stem and progenitor cells (HSPCs) and by analyzing publicly available data from a broad AML patient cohort. We show that patient cells exhibit global 3' untranslated region (UTR) shortening and coding sequence lengthening due to differences in poly(A) site (PAS) usage. Among APA regulators, expression of FIP1L1, one of the core cleavage and polyadenylation factors, correlated with the degree of APA dysregulation in our 3'READS data set. Targeting global APA by FIP1L1 knockdown reversed the global trends seen in patients. Importantly, FIP1L1 knockdown induced differentiation of t(8;21) cells by promoting 3'UTR lengthening and downregulation of the fusion oncoprotein AML1-ETO. In non-t(8;21) cells, FIP1L1 knockdown also promoted differentiation by attenuating mechanistic target of rapamycin complex 1 (mTORC1) signaling and reducing MYC protein levels. Our study provides mechanistic insights into the role of APA in AML pathogenesis and indicates that targeting global APA patterns can overcome the differentiation block in patients with AML.
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