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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. Guttierrez Diaz, Julien Calvo, Celestia Fang, Alireza Khodadadi-Jamayran, et al.
(2020) CANCER DISCOVERY. 10(9). p.1388-1409
Author
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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. 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.
Keywords
Oncology, PRE-MESSENGER-RNA, ACUTE LYMPHOBLASTIC-LEUKEMIA, T-CELL LEUKEMIA, SYNTHETIC LETHAL, SF3B1 MUTATIONS, OVARIAN-CANCER, FACTOR SRSF6, EXPRESSION, GENE, REVEALS

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MLA
Zhou, Yalu, et al. “Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia.” CANCER DISCOVERY, vol. 10, no. 9, 2020, pp. 1388–409, doi:10.1158/2159-8290.cd-19-1436.
APA
Zhou, Y., Han, C., Wang, E., Lorch, A. H., Serafin, V., Cho, B.-K., … Ntziachristos, P. (2020). Posttranslational regulation of the exon skipping machinery controls aberrant splicing in leukemia. CANCER DISCOVERY, 10(9), 1388–1409. https://doi.org/10.1158/2159-8290.cd-19-1436
Chicago author-date
Zhou, Yalu, Cuijuan Han, Eric Wang, Adam H. Lorch, Valentina Serafin, Byoung-Kyu Cho, Blanca T. Guttierrez Diaz, et al. 2020. “Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia.” CANCER DISCOVERY 10 (9): 1388–1409. https://doi.org/10.1158/2159-8290.cd-19-1436.
Chicago author-date (all authors)
Zhou, Yalu, Cuijuan Han, Eric Wang, Adam H. Lorch, Valentina Serafin, Byoung-Kyu Cho, Blanca T. Guttierrez 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, and Panagiotis Ntziachristos. 2020. “Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia.” CANCER DISCOVERY 10 (9): 1388–1409. doi:10.1158/2159-8290.cd-19-1436.
Vancouver
1.
Zhou Y, Han C, Wang E, Lorch AH, Serafin V, Cho B-K, et al. Posttranslational regulation of the exon skipping machinery controls aberrant splicing in leukemia. CANCER DISCOVERY. 2020;10(9):1388–409.
IEEE
[1]
Y. Zhou et al., “Posttranslational regulation of the exon skipping machinery controls aberrant splicing in leukemia,” CANCER DISCOVERY, vol. 10, no. 9, pp. 1388–1409, 2020.
@article{8663522,
  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.

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.}},
  author       = {{Zhou, Yalu and Han, Cuijuan and Wang, Eric and Lorch, Adam H. and Serafin, Valentina and Cho, Byoung-Kyu and Guttierrez Diaz, Blanca T. and Calvo, Julien and Fang, Celestia and Khodadadi-Jamayran, Alireza and Tabaglio, Tommaso and Marier, Christian and Kuchmiy, Anna and Sun, Limin and Yacu, George and Filip, Szymon K. and Jin, Qi and Takahashi, Yoh-hei and Amici, David R. and Rendleman, Emily J. and Rawat, Radhika and Bresolin, Silvia and Paganin, Maddalena and Zhang, Cheng and Li, Hu and Kandela, Irawati and Politanska, Yuliya and Abdala-Valencia, Hiam and Mendillo, Marc L and Zhu, Ping and Palhais, Bruno and Van Vlierberghe, Pieter and Taghon, Tom and Aifantis, Iannis and Goo, Young Ah and Guccione, Ernesto and Heguy, Adriana and Tsirigos, Aristotelis and Wee, Keng Boon and Mishra, Rama K and Pflumio, Francoise and Accordi, Benedetta and Basso, Giuseppe and Ntziachristos, Panagiotis}},
  issn         = {{2159-8274}},
  journal      = {{CANCER DISCOVERY}},
  keywords     = {{Oncology,PRE-MESSENGER-RNA,ACUTE LYMPHOBLASTIC-LEUKEMIA,T-CELL LEUKEMIA,SYNTHETIC LETHAL,SF3B1 MUTATIONS,OVARIAN-CANCER,FACTOR SRSF6,EXPRESSION,GENE,REVEALS}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1388--1409}},
  title        = {{Posttranslational regulation of the exon skipping machinery controls aberrant splicing in leukemia}},
  url          = {{http://doi.org/10.1158/2159-8290.cd-19-1436}},
  volume       = {{10}},
  year         = {{2020}},
}
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