Function and mechanism of PAPOLA-mediated poly(A) lengthening in leukemia [RNA-Seq]

The polyadenylation of mRNA is pivotal for mRNA stability and efficient mRNA translation. The length of poly(A) tail is dynamically changed under various physiological conditions; however, the functions and mechanisms of aberrant poly(A) length control in cancers remain poorly understood. Here we uncovered the aberrant lengthening of poly(A) tail and particularly upregulated expression of poly(A) polymerase alpha (PAPOLA) in acute myeloid leukemia (AML), and the elevated PAPOLA expression significantly correlated with unfavorable AML outcomes. We further demonstrated the critical oncogenic functions of PAPOLA-mediated poly(A) lengthening in promoting AML leukemogenesis and leukemia stem cell self-renewal using human primary AML samples, AML cells and various mouse leukemogenesis models. Mechanistically, we identified GSTM2 as a key downstream target of PAPOLA that regulated metabolic reprogramming through the HNE-DLD axis to promote AML initiation and progression. Moreover, PAPOLA inhibitor cordycepin effectively blocked metabolic reprogramming and AML leukemogenesis in vivo. Overall, our study uncovers the novel functional link between aberrant poly(A) lengthening and cellular metabolic reprogramming in AML, and provides a molecular basis for development of an effective therapeutic strategy for AML patients. Overall design: RNA-Seq was used to study the differentially expressed genes in the PAPOLA knockdown and control cells.mRNA的聚腺苷酸化（polyadenylation）对信使RNA（messenger RNA, mRNA）的稳定性与高效翻译至关重要。poly(A)尾的长度在多种生理条件下呈现动态变化；然而，癌症中异常poly(A)长度调控的功能与机制仍未得到充分阐释。本研究在急性髓系白血病（acute myeloid leukemia, AML）中发现了poly(A)尾的异常延长现象，尤其是聚腺苷酸聚合酶α（poly(A) polymerase alpha, PAPOLA）的表达显著上调，且PAPOLA的高表达与AML患者的不良预后显著相关。研究团队进一步借助人原代AML样本、AML细胞及多种小鼠白血病发生模型，证实了PAPOLA介导的poly(A)尾延长在促进AML白血病发生与白血病干细胞自我更新过程中发挥关键致癌功能。机制层面，本研究鉴定出谷胱甘肽S-转移酶μ2（GSTM2）为PAPOLA的关键下游靶点，其通过HNE-DLD轴调控代谢重编程，进而推动AML的起始与进展。此外，PAPOLA抑制剂虫草素（cordycepin）可有效阻断体内的代谢重编程与AML白血病发生。综上，本研究揭示了AML中异常poly(A)尾延长与细胞代谢重编程之间的新型功能关联，为AML患者的有效治疗策略开发提供了分子基础。整体实验设计：采用RNA测序（RNA-Seq）分析PAPOLA敲低细胞与对照细胞的差异表达基因。

搜集汇总

背景与挑战

背景概述

该数据集包含6个人类RNA-Seq样本，旨在研究白血病中PAPOLA介导的poly(A)尾延长的功能和机制。数据使用BGISEQ-500平台生成，为单端测序，每个样本测序量约1-1.2G bases，包括PAPOLA敲低实验组和阴性对照组，以支持相关分子机制分析。