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The non-canonical BAF chromatin remodeling complex is a novel target of spliceosome dysregulation in SF3B1-mutated chronic lymphocytic leukemia.
Hägerstrand, Daniel; Oder, Blaz; Cortese, Diego; Qu, Ying; Binzer-Panchal, Amrei; Österholm, Cecilia; Del Peso Santos, Teresa; Rabbani, Leily; Asl, Hassan Foroughi; Skaftason, Aron; Ljungström, Viktor; Lundholm, August; Koutroumani, Maria; Haider, Zahra; Jylhä, Cecilia; Mollstedt, John; Mansouri, Larry; Plevova, Karla; Agathangelidis, Andreas; Scarfò, Lydia; Armand, Marine; Muggen, Alice F; Kay, Neil E; Shanafelt, Tait; Rossi, Davide; Orre, Lukas M; Pospisilova, Sarka; Barylyuk, Konstantin; Davi, Frederic; Vesterlund, Mattias; Langerak, Anton W; Lehtiö, Janne; Ghia, Paolo; Stamatopoulos, Kostas; Sutton, Lesley-Ann; Rosenquist, Richard.
Afiliación
  • Hägerstrand D; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Oder B; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Cortese D; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Qu Y; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Binzer-Panchal A; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Österholm C; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Del Peso Santos T; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Rabbani L; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Asl HF; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Skaftason A; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Ljungström V; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Lundholm A; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Koutroumani M; Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece.
  • Haider Z; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Jylhä C; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Mollstedt J; Clinical Genetics and Genomics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.
  • Mansouri L; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Plevova K; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Agathangelidis A; Department of Internal Medicine - Hematology and Oncology, Medical Faculty, Masaryk University and University Hospital Brno, Brno, Czech Republic.
  • Scarfò L; Institute of Medical Genetics and Genomics, Medical Faculty, Masaryk University and University Hospital Brno, Brno, Czech Republic.
  • Armand M; Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
  • Muggen AF; Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece.
  • Kay NE; Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece.
  • Shanafelt T; Università Vita-Salute San Raffaele, Milan, Italy.
  • Rossi D; Division of Experimental Oncology, IRCCS, Ospedale San Raffaele, Milan, Italy.
  • Orre LM; Department of Hematology, Hospital Pitie-Salpetriere, Sorbonne University, Paris, France.
  • Pospisilova S; Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
  • Barylyuk K; Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
  • Davi F; Department of Immunology, Mayo Clinic, Rochester, USA.
  • Vesterlund M; Division of Hematology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA.
  • Langerak AW; Department of Hematology, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland.
  • Lehtiö J; Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
  • Ghia P; Department of Internal Medicine - Hematology and Oncology, Medical Faculty, Masaryk University and University Hospital Brno, Brno, Czech Republic.
  • Stamatopoulos K; Institute of Medical Genetics and Genomics, Medical Faculty, Masaryk University and University Hospital Brno, Brno, Czech Republic.
  • Sutton LA; Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
  • Rosenquist R; Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
Leukemia ; 38(11): 2429-2442, 2024 Nov.
Article en En | MEDLINE | ID: mdl-39261602
ABSTRACT
SF3B1 mutations are recurrent in chronic lymphocytic leukemia (CLL), particularly enriched in clinically aggressive stereotyped subset #2. To investigate their impact, we conducted RNA-sequencing of 18 SF3B1MUT and 17 SF3B1WT subset #2 cases and identified 80 significant alternative splicing events (ASEs). Notable ASEs concerned exon inclusion in the non-canonical BAF (ncBAF) chromatin remodeling complex subunit, BRD9, and splice variants in eight additional ncBAF complex interactors. Long-read RNA-sequencing confirmed the presence of splice variants, and extended analysis of 139 CLL cases corroborated their association with SF3B1 mutations. Overexpression of SF3B1K700E induced exon inclusion in BRD9, resulting in a novel splice isoform with an alternative C-terminus. Protein interactome analysis of the BRD9 splice isoform revealed augmented ncBAF complex interaction, while exhibiting decreased binding of auxiliary proteins, including SPEN, BRCA2, and CHD9. Additionally, integrative multi-omics analysis identified a ncBAF complex-bound gene quartet on chromosome 1 with higher expression levels and more accessible chromatin in SF3B1MUT CLL. Finally, Cancer Dependency Map analysis and BRD9 inhibition displayed BRD9 dependency and sensitivity in cell lines and primary CLL cells. In conclusion, spliceosome dysregulation caused by SF3B1 mutations leads to multiple ASEs and an altered ncBAF complex interactome, highlighting a novel pathobiological mechanism in SF3B1MUT CLL.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfoproteínas / Leucemia Linfocítica Crónica de Células B / Empalmosomas / Ensamble y Desensamble de Cromatina / Factores de Empalme de ARN / Mutación Límite: Humans Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfoproteínas / Leucemia Linfocítica Crónica de Células B / Empalmosomas / Ensamble y Desensamble de Cromatina / Factores de Empalme de ARN / Mutación Límite: Humans Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido