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1. 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
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2. 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
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3. 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
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4. 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
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5. 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
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6. 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
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7. 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
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8. 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
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9. 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
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10. 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
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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
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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
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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
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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
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15. RNA helicase DHX15 exemplifies a unique dependency in acute leukemia

Author

Hao Guo, Jin Xu, Peiqi Xing, Qilong Li, Donghai Wang, Chao Tang, Bruno Palhais, Juliette Roels, Jiaxu Liu, Sa Pan, Jinyan Huang, Zhaoqi Liu, Ping Zhu, Tom Taghon, Guoliang Qing, Pieter Van Vlierberghe, and Hudan Liu

Subjects
Hematology
Abstract

RNA-binding proteins (RBPs) have emerged as essential regulators to control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. Yet implications of essential RBPs during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBPs identifies RNA helicase DHX15, which facilitates the disassembly of spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during CD4-CD8-(DN)-to-CD4+CD8+(DP) transition. Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate prominent anti-T-ALL efficacy. Collectively, we here highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach that splicing perturbation by targeting spliceosome disassembly may achieve considerable anti-tumor efficacy.

Published
2023
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