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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 1241<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-19-1436","type":"journal-article","created":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T14:35:17Z","timestamp":1590158117000},"page":"1388-1409","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia"],"prefix":"10.1158","volume":"10","author":[{"given":"Yalu","family":"Zhou","sequence":"first","affiliation":[{"name":"1Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois."},{"name":"2Simpson Querrey Institute for 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