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

Hexiu Su,Pieter Van Vlierberghe,Yu Zhou,Hudan Liu,Yang Yang,Juncheng Hu,Guoliang Qing,Anna Kuchmiy,Zhichao Chen,Liang Huang,Peng Li,Morgan Thenoz,Tom Taghon,Yufeng Hu,Hui Feng

doi:10.1038/s41467-018-06523-4

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.

Highlights

T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with complicated heterogeneity
Analysis of the Cancer Cell Line Encyclopedia (CCLE) demonstrated SHQ1 is most highly expressed in T-ALL among 1036 human cancer cell lines[21] (Fig. 1b)
We identify a global upregulation of SHQ1 in T-ALL

Summary

Introduction

T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with complicated heterogeneity. We report a mechanism of NOTCH1–SHQ1–MYC axis in T-cell leukemogenesis These findings shed light on the role of SHQ1 in RNA splicing and tumorigenesis, and provide additional insight into MYC regulation. Genome-wide sequencing has identified numerous somatic gene mutations in T-ALL, in which NOTCH1 gain-of-function mutations are found in >50% of TALL cases[5] and FBW7, the gene encoding the NOTCH1 E3 ligase, is mutated with impaired activity at the rate of 12%6,7 These findings have vaulted the dysregulated NOTCH1 signaling to the center of T-ALL pathogenesis[8]. We identify MYC, whose splicing and expression are highly dependent on SHQ1, as an important downstream effector mediating the tumor-supporting role of SHQ1 These findings provide important insights into how SHQ1-mediated RNA modification and pre-mRNA splicing affect tumorigenesis, and deepen our understanding of posttranscriptional regulation of oncogene MYC

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Results

Conclusion