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

Cancer Discov. 2020 Sep;10(9):1388-1409. doi: 10.1158/2159-8290.CD-19-1436. Epub 2020 May 22.


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. 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.This article is highlighted in the In This Issue feature, p. 1241.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alternative Splicing / drug effects
  • Alternative Splicing / genetics*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Drug Synergism
  • Exons / genetics
  • Humans
  • Jurkat Cells
  • Male
  • Mice
  • Phosphoproteins / metabolism*
  • Piperazines / pharmacology
  • Piperazines / therapeutic use
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Proof of Concept Study
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / pharmacology
  • Proteasome Inhibitors / therapeutic use
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Serine-Arginine Splicing Factors / metabolism*
  • Ubiquitin-Specific Peptidase 7 / metabolism*
  • Ubiquitination
  • Xenograft Model Antitumor Assays


  • H3B-8800
  • Phosphoproteins
  • Piperazines
  • Proteasome Inhibitors
  • Pyridines
  • SRSF6 protein, human
  • Serine-Arginine Splicing Factors
  • USP7 protein, human
  • Ubiquitin-Specific Peptidase 7
  • Proteasome Endopeptidase Complex