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1. Supplementary Table 2 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

KEGG Pathway Enrichment Analysis of Differential Expressed Genes Between Thymus and T-ALL

Published
2023

2. Supplementary Table 3 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

KEGG Pathway Enrichment Analysis of Differential Expressed Genes Between CD4 T-Cells and T-ALL

Published
2023

3. Data from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

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

Published
2023

4. Supplementary Table 14 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

Differential Gene Expression and Enrichment Analysis Between Control and shSRSF6-Treated JURKAT Cells

Published
2023

5. Supplementary Figures S1-15 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

Supplementary Figures S1-S15 and Legends

Published
2023

6. Supplementary Table 7 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

Alternative Spliced Genes Between HR and NHR T-ALL Patients and Enrichment Analysis

Published
2023

7. Supplementary Table 10 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

Mutation Status of Selected Splicing Factors in T-ALL patients

Published
2023

8. Supplementary Table 8 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

SRSF Family Proteins Essentiality in Tumor Cell Lines

Published
2023

9. Supplementary Table 12 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

Protein List and Enrichment Analysis of KGG-MS

Published
2023

10. Supplementary Table 6 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

Motif Analysis of Skip Exon Events in T-ALL Compared to CD3 T Cells

Published
2023

11. Supplementary Table 9 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

CRISP Screens of RNA Binding Proteins in T-ALL

Published
2023

12. Supplementary Table 4 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

KEGG Enrichment Analysis of Differential Expressed Genes Between Thymus and T-ALL

Published
2023

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

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

Protein List and Enrichment Analysis of USP7-IP-MS

Published
2023

14. Supplementary Table 13 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author

Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou

Abstract

Gene Ontology Analysis of Overlap Proteins from USP7-IP-MS and KGG-MS

Published
2023

15. Supplementary Table 1 from USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia

Author

Panagiotis Ntziachristos, Ali Shilatifard, John D. Crispino, Suresh Kumar, Joseph Weinstock, Neil L. Kelleher, Giuseppe Basso, Benedetta Accordi, Maddalena Paganin, Silvia Bresolin, Valentina Serafin, Beat Bornhauser, Jean-Pierre Bourquin, Irawati Kandela, Christine Mantis, Beatrix Ueberheide, Stephen Kelly, Alexandros Strikoudis, Pieter Van Vlierberghe, Clayton K. Collings, Elizabeth T. Bartom, Radhika Rawat, Lu Wang, Yoh-hei Takahashi, Emily J. Rendleman, Stacy A. Marshall, Steven Goosens, Geert Berx, Niels Vandamme, Sofie Peirs, Nobuko Hijiya, Nebiyu A. Abshiru, Young Ah Goo, Paul M. Thomas, Ivan Sokirniy, Hui Wang, Charles Grove, Jian Wu, Feng Wang, Andrew G. Volk, Megan R. Johnson, Kenneth K. Wang, Blanca T. Gutierrez-Diaz, Yixing Zhu, Kelly M. Arcipowski, Carlos A. Martinez, and Qi Jin

Abstract

Supplementary Table 1

Published
2023

16. Supplementary Table 2 from USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia

Author

Panagiotis Ntziachristos, Ali Shilatifard, John D. Crispino, Suresh Kumar, Joseph Weinstock, Neil L. Kelleher, Giuseppe Basso, Benedetta Accordi, Maddalena Paganin, Silvia Bresolin, Valentina Serafin, Beat Bornhauser, Jean-Pierre Bourquin, Irawati Kandela, Christine Mantis, Beatrix Ueberheide, Stephen Kelly, Alexandros Strikoudis, Pieter Van Vlierberghe, Clayton K. Collings, Elizabeth T. Bartom, Radhika Rawat, Lu Wang, Yoh-hei Takahashi, Emily J. Rendleman, Stacy A. Marshall, Steven Goosens, Geert Berx, Niels Vandamme, Sofie Peirs, Nobuko Hijiya, Nebiyu A. Abshiru, Young Ah Goo, Paul M. Thomas, Ivan Sokirniy, Hui Wang, Charles Grove, Jian Wu, Feng Wang, Andrew G. Volk, Megan R. Johnson, Kenneth K. Wang, Blanca T. Gutierrez-Diaz, Yixing Zhu, Kelly M. Arcipowski, Carlos A. Martinez, and Qi Jin

Abstract

Supplementary Table 2

Published
2023

17. Figures S1-17 plus legends from USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia

Author

Panagiotis Ntziachristos, Ali Shilatifard, John D. Crispino, Suresh Kumar, Joseph Weinstock, Neil L. Kelleher, Giuseppe Basso, Benedetta Accordi, Maddalena Paganin, Silvia Bresolin, Valentina Serafin, Beat Bornhauser, Jean-Pierre Bourquin, Irawati Kandela, Christine Mantis, Beatrix Ueberheide, Stephen Kelly, Alexandros Strikoudis, Pieter Van Vlierberghe, Clayton K. Collings, Elizabeth T. Bartom, Radhika Rawat, Lu Wang, Yoh-hei Takahashi, Emily J. Rendleman, Stacy A. Marshall, Steven Goosens, Geert Berx, Niels Vandamme, Sofie Peirs, Nobuko Hijiya, Nebiyu A. Abshiru, Young Ah Goo, Paul M. Thomas, Ivan Sokirniy, Hui Wang, Charles Grove, Jian Wu, Feng Wang, Andrew G. Volk, Megan R. Johnson, Kenneth K. Wang, Blanca T. Gutierrez-Diaz, Yixing Zhu, Kelly M. Arcipowski, Carlos A. Martinez, and Qi Jin

Abstract

Supplementary Figs. 1-17 with legends

Published
2023

18. Data from USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia

Author

Panagiotis Ntziachristos, Ali Shilatifard, John D. Crispino, Suresh Kumar, Joseph Weinstock, Neil L. Kelleher, Giuseppe Basso, Benedetta Accordi, Maddalena Paganin, Silvia Bresolin, Valentina Serafin, Beat Bornhauser, Jean-Pierre Bourquin, Irawati Kandela, Christine Mantis, Beatrix Ueberheide, Stephen Kelly, Alexandros Strikoudis, Pieter Van Vlierberghe, Clayton K. Collings, Elizabeth T. Bartom, Radhika Rawat, Lu Wang, Yoh-hei Takahashi, Emily J. Rendleman, Stacy A. Marshall, Steven Goosens, Geert Berx, Niels Vandamme, Sofie Peirs, Nobuko Hijiya, Nebiyu A. Abshiru, Young Ah Goo, Paul M. Thomas, Ivan Sokirniy, Hui Wang, Charles Grove, Jian Wu, Feng Wang, Andrew G. Volk, Megan R. Johnson, Kenneth K. Wang, Blanca T. Gutierrez-Diaz, Yixing Zhu, Kelly M. Arcipowski, Carlos A. Martinez, and Qi Jin

Abstract

Purpose:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes.Experimental Design:To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models.Results:We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo.Conclusions:These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.

Published
2023

19. Deubiquitinases: Pro-oncogenic Activity and Therapeutic Targeting in Blood Malignancies

Author

Wei Gu, Panagiotis Ntziachristos, and Blanca T. Gutierrez-Diaz

Subjects
0301 basic medicine, Disease outcome, Immunology, Therapeutic targeting, 03 medical and health sciences, 0302 clinical medicine, Ubiquitin, Neoplasms, medicine, Humans, Immunology and Allergy, Cellular proteins, Acute leukemia, Deubiquitinating Enzymes, biology, Human blood, business.industry, Cancer, medicine.disease, Leukemia, 030104 developmental biology, Hematologic Neoplasms, Cancer research, biology.protein, business, 030215 immunology
Abstract

Deubiquitinases are enzymes that remove ubiquitin moieties from the vast majority of cellular proteins, controlling their stability, interactions, and localization. The expression and activity of deubiquitinases are critical for physiology and can go awry in various diseases, including cancer. Based on recent findings in human blood cancers, we discuss the functions of selected deubiquitinases in acute leukemia and efforts to target these enzymes with the aim of blocking leukemia growth and improving disease outcomes. We focus on the emergence of the newest generation of preclinical inhibitors by discussing their modes of inhibition and their effects on leukemia biology.

Published
2020

20. SF3B1 homeostasis is critical for survival and therapeutic response in T cell leukemia

Author

Cuijuan Han, Alireza Khodadadi-Jamayran, Adam H. Lorch, Qi Jin, Valentina Serafin, Ping Zhu, Yuliya Politanska, Limin Sun, Blanca T. Gutierrez-Diaz, Marina V. Pryzhkova, Hiam Abdala-Valencia, Elizabeth Thomas Bartom, Barbara Buldini, Giuseppe Basso, Sadanandan E. Velu, Kavitha Sarma, Basil B. Mattamana, Byoung-Kyu Cho, Rebecca C. Obeng, Young Ah Goo, Philip W. Jordan, Aristotelis Tsirigos, Yalu Zhou, and Panagiotis Ntziachristos

Subjects
Leukemia, T-Cell, Multidisciplinary, SciAdv r-articles, Phosphoproteins, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Mutation, Medicine and Health Sciences, Homeostasis, Humans, RNA Splicing Factors, Biomedicine and Life Sciences, Molecular Biology, Research Article, Cancer
Abstract

The production of noncanonical mRNA transcripts is associated with cell transformation. Driven by our previous findings on the sensitivity of T cell acute lymphoblastic leukemia (T-ALL) cells to SF3B1 inhibitors, we identified that SF3B1 inhibition blocks T-ALL growth in vivo with no notable associated toxicity. We also revealed protein stabilization of the U2 complex component SF3B1 via deubiquitination. Our studies showed that SF3B1 inhibition perturbs exon skipping, leading to nonsense-mediated decay and diminished levels of DNA damage response–related transcripts, such as the serine/threonine kinase CHEK2, and impaired DNA damage response. We also identified that SF3B1 inhibition leads to a general decrease in R-loop formation. We further demonstrate that clinically used SF3B1 inhibitors synergize with CHEK2 inhibitors and chemotherapeutic drugs to block leukemia growth. Our study provides the proof of principle for posttranslational regulation of splicing components and associated roles and therapeutic implications for the U2 complex in T cell leukemia., Description, The splicing factor SF3B1 is regulated at the protein level and is a therapeutic target in T cell leukemia.

Published
2022

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