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2. Myb overexpression synergizes with the loss of Pten and is a dependency factor and therapeutic target in T‐cell lymphoblastic leukemia

Author

André Almeida, Sara T'Sas, Luca Pagliaro, Igor Fijalkowski, Wouter Sleeckx, Hannah Van Steenberge, Raffaella Zamponi, Béatrice Lintermans, Wouter Van Loocke, Bruno Palhais, Alexandra Reekmans, Valentina Bardelli, Lisa Demoen, Lindy Reunes, Dieter Deforce, Filip Van Nieuwerburgh, Alex Kentsis, Panagiotis Ntziachristos, Nadine Van Roy, Barbara De Moerloose, Cristina Mecucci, Roberta La Starza, Giovanni Roti, Steven Goossens, Pieter Van Vlierberghe, and Tim Pieters

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract T‐lineage acute lymphoblastic leukemia (T‐ALL) is an aggressive hematological malignancy that accounts for 10%–15% of pediatric and 25% of adult ALL cases. Although the prognosis of T‐ALL has improved over time, the outcome of T‐ALL patients with primary resistant or relapsed leukemia remains poor. Therefore, further progress in the treatment of T‐ALL requires a better understanding of its biology and the development of more effective precision oncologic therapies. The proto‐oncogene MYB is highly expressed in diverse hematologic malignancies, including T‐ALLs with genomic aberrations that further potentiate its expression and activity. Previous studies have associated MYB with a malignant role in the pathogenesis of several cancers. However, its role in the induction and maintenance of T‐ALL remains relatively poorly understood. In this study, we found that an increased copy number of MYB is associated with higher MYB expression levels, and might be associated with inferior event‐free survival of pediatric T‐ALL patients. Using our previously described conditional Myb overexpression mice, we generated two distinct MYB‐driven T‐ALL mouse models. We demonstrated that the overexpression of Myb synergizes with Pten deletion but not with the overexpression of Lmo2 to accelerate the development of T‐cell lymphoblastic leukemias. We also showed that MYB is a dependency factor in T‐ALL since RNA interference of Myb blocked cell cycle progression and induced apoptosis in both human and murine T‐ALL cell lines. Finally, we provide preclinical evidence that targeting the transcriptional activity of MYB can be a useful therapeutic strategy for the treatment of T‐ALL.

Published
2024
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3. Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma

Author

Stien De Coninck, Renate De Smedt, Beatrice Lintermans, Lindy Reunes, Hansen J. Kosasih, Alexandra Reekmans, Lauren M. Brown, Nadine Van Roy, Bruno Palhais, Juliette Roels, Malaika Van der Linden, Jo Van Dorpe, Panagiotis Ntziachristos, Frederik W. van Delft, Marc R. Mansour, Tim Pieters, Tim Lammens, Barbara De Moerloose, Charles E. de Bock, Steven Goossens, and Pieter Van Vlierberghe

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are rare aggressive hematologic malignancies. Current treatment consists of intensive chemotherapy leading to 80% overall survival but is associated with severe toxic side effects. Furthermore, 10-20% of patients still die from relapsed or refractory disease providing a strong rationale for more specific, targeted therapeutic strategies with less toxicities. Here, we report a novel MYH9::PDGFRB fusion in a T-LBL patient, and demonstrate that this fusion product is constitutively active and sufficient to drive oncogenic transformation in vitro and in vivo. Expanding our analysis more broadly across T-ALL, we found a T-ALL cell line and multiple patient-derived xenograft models with PDGFRB hyperactivation in the absence of a fusion, with high PDGFRB expression in TLX3 and HOXA T-ALL molecular subtypes. To target this PDGFRB hyperactivation, we evaluated the therapeutic effects of a selective PDGFRB inhibitor, CP-673451, both in vitro and in vivo and demonstrated sensitivity if the receptor is hyperactivated. Altogether, our work reveals that hyperactivation of PDGFRB is an oncogenic driver in T-ALL/T-LBL, and that screening T-ALL/T-LBL patients for phosphorylated PDGFRB levels can serve as a biomarker for PDGFRB inhibition as a novel targeted therapeutic strategy in their treatment regimen.

Published
2023
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4. 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
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

RNA-binding proteins (RBP) have emerged as essential regulators that control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. The implications of essential RBP during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBP identifies RNA helicase DHX15, which facilitates the disassembly of the 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 the transition from doublenegative to double-positive cells (CD4-CD8- to CD4+CD8+). 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 that it has prominent anti-T-ALL efficacy. Collectively, our data highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach, i.e., splicing perturbation by targeting spliceosome disassembly, may achieve considerable anti-tumor efficacy.

Published
2023
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5. 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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6. 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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7. 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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8. 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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9. 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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10. 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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11. 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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12. 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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13. 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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14. 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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15. Splice-shifting oligonucleotide (SSO) mediated blocking of an exonic splicing enhancer (ESE) created by the prevalent c.903+469T>C MTRR mutation corrects splicing and restores enzyme activity in patient cells

Author

Rugivan Sabaratnam, Bruno Palhais, Veronica S. Præstegaard, Henriette Skovgaard Andersen, Viktor Kožich, Patricie Burda, Thomas Koed Doktor, Seraina Lutz, Brian Fowler, Gitte Hoffmann Bruun, Terttu Suormala, Matthias R. Baumgartner, Brage S. Andresen, University of Zurich, and Andresen, Brage Storstein

Subjects
Anemia, Megaloblastic, RNA Splicing, Oligonucleotides, Exonic splicing enhancer, 610 Medicine & health, Regulatory Sequences, Ribonucleic Acid, Biology, medicine.disease_cause, Cell Line, Exon, 1311 Genetics, Genetics, medicine, Humans, Exonic splicing silencer, Cells, Cultured, Mutation, Point mutation, Exons, MTRR, Ferredoxin-NADP Reductase, HEK293 Cells, 10036 Medical Clinic, Regulatory sequence, RNA splicing, RNA, Homocystinuria, RNA Splice Sites
Abstract

The prevalent c.903+469T>C mutation in MTRR causes the cblE type of homocystinuria by strengthening an SRSF1 binding site in an ESE leading to activation of a pseudoexon. We hypothesized that other splicing regulatory elements (SREs) are also critical for MTRR pseudoexon inclusion. We demonstrate that the MTRR pseudoexon is on the verge of being recognized and is therefore vulnerable to several point mutations that disrupt a fine-tuned balance between the different SREs. Normally, pseudoexon inclusion is suppressed by a hnRNP A1 binding exonic splicing silencer (ESS). When the c.903+469T>C mutation is present two ESEs abrogate the activity of the ESS and promote pseudoexon inclusion. Blocking the 3′splice site or the ESEs by SSOs is effective in restoring normal splicing of minigenes and endogenous MTRR transcripts in patient cells. By employing an SSO complementary to both ESEs, we were able to rescue MTRR enzymatic activity in patient cells to approximately 50% of that in controls. We show that several point mutations, individually, can activate a pseudoexon, illustrating that this mechanism can occur more frequently than previously expected. Moreover, we demonstrate that SSO blocking of critical ESEs is a promising strategy to treat the increasing number of activated pseudoexons.

Published
2017
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