SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival

Hexiu Su, Juncheng Hu, Liang Huang, Yang Yang, Morgan Thenoz, Anna Kuchmiy, Yufeng Hu, Peng Li, Hui Feng, Yu Zhou, Tom Taghon, Pieter Van Vlierberghe, Guoliang Qing, Zhichao Chen () and Hudan Liu ()
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Hexiu Su: Huazhong University of Science and Technology
Juncheng Hu: Wuhan University
Liang Huang: Huazhong University of Science and Technology
Yang Yang: Wuhan University
Morgan Thenoz: Ghent University
Anna Kuchmiy: Ghent University
Yufeng Hu: Zhongnan Hospital of Wuhan University
Peng Li: Chinese Academy of Sciences
Hui Feng: Boston University School of Medicine
Yu Zhou: Wuhan University
Tom Taghon: Ghent University
Pieter Van Vlierberghe: Ghent University
Guoliang Qing: Wuhan University
Zhichao Chen: Huazhong University of Science and Technology
Hudan Liu: Wuhan University

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with complicated heterogeneity. Although expression profiling reveals common elevated genes in distinct T-ALL subtypes, little is known about their functional role(s) and regulatory mechanism(s). We here show that SHQ1, an H/ACA snoRNP assembly factor involved in snRNA pseudouridylation, is highly expressed in T-ALL. Mechanistically, oncogenic NOTCH1 directly binds to the SHQ1 promoter and activates its transcription. SHQ1 depletion induces T-ALL cell death in vitro and prolongs animal survival in murine T-ALL models. RNA-Seq reveals that SHQ1 depletion impairs widespread RNA splicing, and MYC is one of the most prominently downregulated genes due to inefficient splicing. MYC overexpression significantly rescues T-ALL cell death resulted from SHQ1 inactivation. We herein report a mechanism of NOTCH1–SHQ1–MYC axis in T-cell leukemogenesis. These findings not only shed light on the role of SHQ1 in RNA splicing and tumorigenesis, but also provide additional insight into MYC regulation.

Date: 2018
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DOI: 10.1038/s41467-018-06523-4

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