SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival.
Nat Commun. 2018 Oct 15;9(1):4281. doi: 10.1038/s41467-018-06523-4.
SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival.
Su H
1,
2,
Hu J
2,
Huang L
3,
Yang Y
4,
Thenoz M
5,
Kuchmiy A
6,
Hu Y
7,
Li P
8,
Feng H
9,
Zhou Y
4,
Taghon T
6,
Van Vlierberghe P
5,
Qing G
2,
7,
Chen Z
10,
Liu H
11,
12.
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.