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Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139622 | GEO | 2020/06/01

REPOSITORIES: GEO

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Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia.

Project description:Splicing alterations are common in diseases such as cancer, where mutations in splicing factor genes are frequently responsible for aberrant splicing. Here we present an alternative mechanism for splicing regulation in T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the splicing machinery via deubiquitination. We demonstrate there are extensive exon skipping changes in disease, affecting proteasomal subunits, cell-cycle regulators, and the RNA machinery. We present that the serine/arginine-rich splicing factors (SRSF), controlling exon skipping, are critical for leukemia cell survival. The ubiquitin-specific peptidase 7 (USP7) regulates SRSF6 protein levels via active deubiquitination, and USP7 inhibition alters the exon skipping pattern and blocks T-ALL growth. The splicing inhibitor H3B-8800 affects splicing of proteasomal transcripts and proteasome activity and acts synergistically with proteasome inhibitors in inhibiting T-ALL growth. Our study provides the proof-of-principle for regulation of splicing factors via deubiquitination and suggests new therapeutic modalities in T-ALL. SIGNIFICANCE: Our study provides a new proof-of-principle for posttranslational regulation of splicing factors independently of mutations in aggressive T-cell leukemia. It further suggests a new drug combination of splicing and proteasomal inhibitors, a concept that might apply to other diseases with or without mutations affecting the splicing machinery.This article is highlighted in the In This Issue feature, p. 1241.

| S-EPMC7483384 | biostudies-literature

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [CUTLL1_P5091]

Project description:In this study, we show that pediatric T-cell acute lymphoblastic leukemia (T-ALL) has an alternative mechanism for aberrant splicing that involves post-translational regulation of the splicing machinery via deubiquitination.

2020-06-01 | GSE139620 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_P5091]

2020-06-01 | GSE139619 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_shSRSF6]

2020-06-01 | GSE139621 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia

Project description:Splicing alterations are very common in cancer and might affect disease initiation and progression. In several cancers, mutations in splicing factor genes are responsible for aberrant splicing. We show that certain aggressive cancers, such as pediatric T-cell acute lymphoblastic leukemia (T-ALL), have an alternative mechanism for aberrant splicing that involves post-translational regulation of the splicing machinery via deubiquitination. We initially demonstrated that T-ALL presents with extensive exon skipping events affecting proteasomal transcripts, cell cycle and epigenetic regulators. Performing an unbiased genetic screen study for RNA binding proteins, we showed that the serine/arginine-rich splicing factor (SRSF) proteins, controlling exon skipping are critical for T-ALL survival. In our effort to dissect mechanisms of aberrant regulation of SRSF proteins, we focused on the pro-oncogenic deubiquitinase ubiquitin-specific peptidase 7 (USP7) to show it regulates the levels of the SRSF proteins at the post-translational level via active deubiquitination. We further demonstrated that USP7 inhibitors can change the splicing landscape and block T-ALL growth. Our drug studies show that decrease of the levels of SRSF proteins splicing inhibitors sensitize cells to the clinically used splicing inhibitor H3B-8800. Driven by our molecular findings on aberrant splicing of proteasomal transcripts, we demonstrate that H3B-8800 could act synergistically with proteasome inhibitors, paving the way for new therapeutic schemes in pediatric leukemia. Collectively this study provides the proof-of-principle for regulation of splicing factors independently of mutations and via deubiquitination and suggests new therapeutic modalities and combinations in cancer.

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Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [CUTLL1_H3B-8800]

2020-06-01 | GSE139616 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Patients II]

2020-06-01 | GSE139614 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Patients I]

2020-06-01 | GSE139613 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_H3B-8800 6hr]

2020-06-01 | GSE139617 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_H3B-8800 24h]

2020-06-01 | GSE139618 | GEO