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Overexpression of c-Myc-dependent Heterogeneous nuclear ribonucleoprotein A1 promotes proliferation and inhibits apoptosis in NOTCH1-mutated chronic lymphocytic leukemia cells

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Chinese Medical Journal 2022年第8期135卷 920-929页

作者： Yixin Zou Hanning Tang Yi Miao Huayuan Zhu Li Wang Lei Fan Jianxin Fu Wei Xu Jianyong Li Yi Xia department of Hematology The First Affiliated Hospital of Nanjing Medical UniversityJiangsu Province HospitalNanjingJiangsu 210029China Key Laboratory of Hematology of Nanjing Medical University NanjingJiangsu 210029China Collaborative Innovation Center for Cancer Personalized Medicine NanjingJiangsu 210029China Pukou CLL Center NanjingJiangsu 210000China

Background: NOTCH1 mutation is an essential molecular biologic aberration in chronic lymphocytic leukemia (CLL). CLL patients withNOTCH1 mutation have shown an unfavorable survival and a poor response to chemoimmunotherapy. This study aims to present the mechanisms of adverse prognosis caused byNOTCH1 mutation from the perspective of the splicing factor Heterogeneous nuclear ribonucleoprotein A1 (hnRNPa1).Methods: The microarray data in Gene Expression Omnibus datasets were analyzed by bioinformatics and the function of hnRNPa1 was checked by testing the proliferation and apoptosis of CLL-like cell lines. Afterward, quantitative reverse transcription-polymerase chain reaction and Western blotting were applied to explore the relationship among NOTCH1, c-Myc, and hnRNPa1.Results: RNA splicing was found to play a vital part inNOTCH1-mutated CLL cells;hence, hnRNPa1 was selected as the focus of this study. Higher expression of hnRNPa1 validated in primaryNOTCH1-mutated CLL samples could promote proliferation and inhibit apoptosis in CLL. The expression of hnRNPa1 increased when NOTCH1 signaling was activated by transfection with NOTCH1 intracellular domain (NICD)-overexpressed adenovirus vector and declined after NOTCH1 signaling was inhibited by NOTCH1-shRNA. Higher expression of c-Myc was observed in NICD-overexpressed cells and hnRNPa1 expression was downregulated after applying c-Myc inhibitor 10058-F4. Moreover, in NICD-overexpressed cells, hnRNPa1 expression decreased through c-Myc inhibition.Conclusion: Overexpression of c-Myc-dependent hnRNPa1 could promote proliferation and inhibit apoptosis inNOTCH1- mutated CLL cells, which might partly account for the poor prognosis of patients withNOTCH1 mutation.

关键词： Chronic lymphocytic leukemia NOTCH1 mutation c-Myc Heterogeneous nuclear ribonucleoprotein A1

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