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

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Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia Published OnlineFirst May 22, 2020; DOI: 10.1158/2159-8290.CD-19-1436 RESEARCH ARTICLE Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia Yalu Zhou1,2, Cuijuan Han1,2, Eric Wang3, Adam H. Lorch1,2, Valentina Serafin4, Byoung-Kyu Cho5, Blanca T. Gutierrez Diaz1,2, Julien Calvo6,7, Celestia Fang1,2,8, Alireza Khodadadi-Jamayran9, Tommaso Tabaglio10,11, Christian Marier12, Anna Kuchmiy13,14, Limin Sun1,2, George Yacu1,2, Szymon K. Filip5, Qi Jin1,2, Yoh-Hei Takahashi1,2, David R. Amici1,2,8, Emily J. Rendleman1,2, Radhika Rawat1,2,8, Silvia Bresolin4, Maddalena Paganin4, Cheng Zhang15, Hu Li15, Irawati Kandela16, Yuliya Politanska17, Hiam Abdala-Valencia17, Marc L. Mendillo1,2, Ping Zhu18, Bruno Palhais13,19, Pieter Van Vlierberghe13,19, Tom Taghon13,14,20, Iannis Aifantis3, Young Ah Goo1,5, Ernesto Guccione21,22, Adriana Heguy3,12, Aristotelis Tsirigos3,9, Keng Boon Wee10,11, Rama K. Mishra1,23, Francoise Pflumio6,7, Benedetta Accordi4, Giuseppe Basso4, and Panagiotis Ntziachristos1,2,24 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 splic- ing 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. 1Department of Biochemistry and Molecular Genetics, Northwestern 9Applied Bioinformatics Laboratories, Office of Science and Research, University, Chicago, Illinois. 2Simpson Querrey Institute for Epigenetics, New York University School of Medicine, New York, New York. 10Institute of Northwestern University Feinberg School of Medicine, Chicago, Illinois. Molecular and Cell Biology, Agency for Science, Technology and Research, 3Department of Pathology and Laura & Isaac Perlmutter Cancer Center, Singapore. 11Department of Biochemistry, Yong Loo Lin School of Medicine, New York University School of Medicine, New York, New York. 4Oncohema- National University of Singapore, Singapore. 12Genome Technology Center, tology Laboratory, Department of Women’s and Children’s Health, University New York University School of Medicine, New York, New York. 13Cancer of Padova, Padova, Italy. 5Proteomics Center of Excellence, Northwestern Research Institute Ghent (CRIG), Ghent, Belgium. 14Department of University, Evanston, Illinois. 6Team Niche and Cancer in hematopoiesis, Diagnostic Sciences, Ghent University, Ghent, Belgium. 15Department CEA, Fontenay-aux-Roses, France. 7Laboratory of Hematopoietic Stem of Molecular Pharmacology and Experimental Therapeutics, Mayo Cells and Leukemia/Service Stem Cells and Radiation/iRCM/JACOB/DRF, Clinic, Rochester, Minnesota. 16Center for Developmental Therapeutics, CEA, Fontenay-aux-Roses, France. 8Medical Scientist Training Program, Northwestern University, Evanston, Illinois. 17Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Northwestern University Feinberg School of Medicine, Chicago, Illinois. 1388 | CANCER DISCOVERY SEPTEMBER 2020 AACRJournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst May 22, 2020; DOI: 10.1158/2159-8290.CD-19-1436 INTRODUCTION The prevalence of these anomalies in the splicing machin- ery is elevated in certain types of hematologic malignancies Alternative splicing is a critical mechanism of posttran- and provides a unique opportunity for therapeutic targeting scriptional regulation that is mediated by the ribonucleo- (2–4). protein complex commonly known as the spliceosome. It is The splicing machinery is frequently mutated in the early estimated that more than 90% of transcripts from multiex- stages of many types of cancer, such as myelodysplastic syn- onic protein-coding transcripts could be alternatively spliced dromes or chronic lymphocytic leukemia, demonstrating the in a tissue- or developmental stage–specific manner, under importance of this pathway for cellular function (2–13). Aber- stress or in disease (1). Whereas the average human gene rant splicing is mostly attributed to genetic alterations affect- produces three or more alternatively spliced mRNA isoforms, ing the splicing factor genes. These mutations occur most malignant cells produce a significant surplus of splice vari- commonly in splicing factor 3b subunit 1 (SF3B1), serine/ ants. These atypical splice variants appear to be products of arginine-rich splicing factor 2 (SRSF2), zinc finger RNA bind- missplicing that in many cases are secondary to either muta- ing motif and serine/arginine rich 2 (ZRSR2), and U2 small tions in splicing factors or dysregulation of their expression. nuclear RNA auxiliary factor 1 (U2AF1) and in a mutually 18H3 Biomedicine, Inc., Cambridge, Massachusetts. 19Department of Bio- Note: Supplementary data for this article are available at Cancer Discovery molecular Medicine, Ghent University, Ghent, Belgium. 20Faculty of Medi- Online (http://cancerdiscovery.aacrjournals.org/). 21 cine and Health Sciences, Ghent University, Ghent, Belgium. Department Corresponding Author: Panagiotis Ntziachristos, Northwestern University of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medi- Feinberg School of Medicine, 303 East Superior Street, SQBR 7-304, 22 cine at Mount Sinai, New York, New York. Department of Pharmacological Chicago, IL 60611. Phone: 347-703-0048; Fax: 312-503-4081; E-mail: Sciences and Mount Sinai Center for Therapeutics Discovery, Icahn School [email protected] of Medicine at Mount Sinai, New York, New York. 23Center for Molecular Innovation and Drug Discovery, Northwestern University, Chicago, Illinois. Cancer Discov 2020;10:1388–409 24Robert H. Lurie Comprehensive Cancer Center, Northwestern University, doi: 10.1158/2159-8290.CD-19-1436 Chicago, Illinois. ©2020 American Association for Cancer Research. September 2020 CANCER DISCOVERY | 1389 Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst May 22, 2020; DOI: 10.1158/2159-8290.CD-19-1436 RESEARCH ARTICLE Zhou et al. exclusive fashion, as mutations in more than one factor are acterized due to the absence of appropriate leukemia models lethal for tumor and normal cells alike (14). In addition, and needed technologies. mutations affecting RNAs that are part of the spliceosome Although we and others have previously demonstrated were recently identified (15). However, splicing abnormalities the role of epigenetic factors and oncogenic long noncod- found in cancer are not always associated with mutations ing RNAs in T-ALL (40–42), the role of aberrant splicing in these or related genes. Instead, they may arise from aber- and mechanisms of abnormal posttranslational regulation rant expression of splicing factors (16–25). Certain serine/ of the splicing machinery in T-ALL progression have been arginine-rich (SR) splicing factor proteins are overexpressed relatively uncharacterized. In this study, we sought to char- in human cancers, notably SRSF1 (16–19, 25), SRSF6 (16, acterize splicing alterations in T-ALL, potential mechanisms 20, 21), and SRSF3 (22–24). Part of this activation might be regulating aberrant splicing, and their implications for T-ALL due to gene amplification as well as transcriptional regula- biology. tion, mainly through MYC. Expression-related variations in splicing are mostly observed in solid tumors of adult origin, RESULTS suggesting a potential explanation for differences in splicing biology between solid and blood-based cancers. T-ALL Is Characterized by Significant Splicing Acute lymphoblastic leukemia (ALL) is an aggressive pedi- Changes Compared with Physiologic T Cells atric and adult type of leukemia of T and B cell origin, To characterize the splicing landscape in different types of translating to approximately 3,100 children and adolescents human peripheral CD3+ (CD4+/CD8+) T cells, in comparison diagnosed with the disease each year in the United States. with 3 patients with T-cell leukemia, we performed paired- T-cell ALL (T-ALL) is driven by the hyperactivation of path- end sequencing of the transcriptome to cover the splicing ways such as NOTCH1 (26–31), and the incidence of this junctions. To study any T cell subtype–specific
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