Supplementary Table 11 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

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posted on 2023-04-03, 22:24 authored by 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. Rendleman, Radhika 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

Protein List and Enrichment Analysis of USP7-IP-MS

Funding

NCI

CCSG

Comprehensive Cancer Center

Translational and Developmental Proteomics

American Cancer Society

St. Baldrick's Foundation

NIH

European Research Council

NYU Cancer Center

History

ARTICLE 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 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. 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

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Keywords

Hematological Cancers Leukemias Progression, Invasion & Metastasis Tumor progression

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CC BY

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