SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival
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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 the expression of SHQ1, an H/ACA snoRNPs assembly factor involved in snRNA pseudouridylation, is specifically and highly expressed in T-ALL. Mechanistically, oncogenic NOTCH1 directly binds to the SHQ1 promoter and activates its transcription. SHQ1 depletion induces massive leukemia cell death in vitro and in vivo, 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. Ectopically expressed MYC significantly rescues T-ALL cell death resulted from SHQ1 inactivation. We herein report a previously unsuspected mechanism of NOTCH1-SHQ1-MYC axis in T cell leukemogenesis. Our findings not only shed light on the role of SHQ1 in promoting RNA splicing and tumorigenesis, but also provide a new mechanism of MYC regulation.
ORGANISM(S): Homo sapiens
PROVIDER: GSE117264 | GEO | 2018/10/23
REPOSITORIES: GEO
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