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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.

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