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GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies.
Benbarche, Salima; Pineda, Jose Mario Bello; Galvis, Laura Baquero; Biswas, Jeetayu; Liu, Bo; Wang, Eric; Zhang, Qian; Hogg, Simon J; Lyttle, Kadeen; Dahi, Ariana; Lewis, Alexander M; Sarchi, Martina; Rahman, Jahan; Fox, Nina; Ai, Yuxi; Mehta, Sanjoy; Garippa, Ralph; Ortiz-Pacheco, Juliana; Li, Zhuoning; Monetti, Mara; Stanley, Robert F; Doulatov, Sergei; Bradley, Robert K; Abdel-Wahab, Omar.
Afiliación
  • Benbarche S; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Pineda JMB; Public Health Sciences and Basic Sciences Divisions, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA; Medical Scientist Training Program, University of Washington, Seattle, WA, USA.
  • Galvis LB; Division of Hematology/Oncology, Department of Medicine, Department of Genome Sciences, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
  • Biswas J; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Liu B; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Wang E; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • Zhang Q; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Hogg SJ; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Lyttle K; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Dahi A; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Lewis AM; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Sarchi M; Division of Hematology/Oncology, Department of Medicine, Department of Genome Sciences, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
  • Rahman J; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Fox N; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Ai Y; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Mehta S; Gene Editing and Screening Core Facility, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Institute and Cancer Center, New York, NY, USA.
  • Garippa R; Gene Editing and Screening Core Facility, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Institute and Cancer Center, New York, NY, USA.
  • Ortiz-Pacheco J; Proteomics Innovation Laboratory, Memorial Sloan Kettering Institute and Cancer Center, New York, NY, USA.
  • Li Z; Proteomics Innovation Laboratory, Memorial Sloan Kettering Institute and Cancer Center, New York, NY, USA.
  • Monetti M; Proteomics Innovation Laboratory, Memorial Sloan Kettering Institute and Cancer Center, New York, NY, USA.
  • Stanley RF; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Doulatov S; Division of Hematology/Oncology, Department of Medicine, Department of Genome Sciences, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
  • Bradley RK; Public Health Sciences and Basic Sciences Divisions, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA. Electronic address: rbradley@fredhutch.org.
  • Abdel-Wahab O; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: abdelwao@mskcc.org.
Mol Cell ; 84(10): 1886-1903.e10, 2024 May 16.
Article en En | MEDLINE | ID: mdl-38688280
ABSTRACT
Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfoproteínas / Neoplasias Hematológicas / Factores de Empalme de ARN / Proteínas Musculares / Mutación Límite: Animals / Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfoproteínas / Neoplasias Hematológicas / Factores de Empalme de ARN / Proteínas Musculares / Mutación Límite: Animals / Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos