Posttranslational regulation of the exon skipping machinery controls aberrant splicing in leukemia

Yalu Zhou, Cuijuan Han, Eric Wang, Adam H. Lorch, Valentina Serafin, Byoung Kyu Cho, Blanca T. Gutierrez Diaz, Julien Calvo, Celestia Fang, Alireza Khodadadi-Jamayran, Tommaso Tabaglio, Christian Marier, Anna Kuchmiy, Limin Sun, George Yacu, Szymon K. Filip, Qi Jin, Yoh Hei Takahashi, David R. Amici, Emily J. RendlemanRadhika Rawat, Silvia Bresolin, Maddalena Paganin, Cheng Zhang, Hu Li, Irawati Kandela, Yuliya Politanska, Hiam Abdala-Valencia, Marc L. Mendillo, Ping Zhu, Bruno Palhais, Pieter Van Vlierberghe, Tom Taghon, Iannis Aifantis, Young Ah Goo, Ernesto Guccione, Adriana Heguy, Aristotelis Tsirigos, Keng Boon Wee, Rama K. Mishra, Francoise Pflumio, Benedetta Accordi, Giuseppe Basso, Panagiotis Ntziachristos

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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 pepti-dase 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.

Original languageEnglish (US)
Pages (from-to)1388-1410
Number of pages23
JournalCancer discovery
Volume10
Issue number9
DOIs
StatePublished - Sep 2020

ASJC Scopus subject areas

  • Oncology

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