Posttranslational regulation of the exon skipping machinery controls aberrant splicing in leukemia
Description
The unprocessed ("raw") and/or processed data deposited here correspond to the Cancer Discovery paper with the same title (see PMID: 32444465. DOI: 10.1158/2159-8290.CD-19-1436). For the code used in data analysis please see github: https://github.com/NtziachristosLab/SRSF6_T-ALL_CD All the sequencing data are deposited in Gene Expression Omnibus (GEO, GSE139622). All proteomics data are deposited in MassIVE (MSV000084383). For details on methods and how to reproduce the studies please see the methods section on the corresponding manuscript (PMID: 32444465. DOI: 10.1158/2159-8290.CD-19-1436) and/or contact the authors directly. Corresponding author: Panos Ntziachristos, pntziachr@gmail.com. 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.
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Steps to reproduce
Please see methods in the Cancer Discovery manuscript: doi: 10.1158/2159-8290.CD-19-1436. For the code used in data analysis please see github: https://github.com/NtziachristosLab/SRSF6_T-ALL_CD