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The non-canonical BAF chromatin remodeling complex is a novel target of spliceosome dysregulation in SF3B1-mutated chronic lymphocytic leukemia
D. Hägerstrand, B. Oder, D. Cortese, Y. Qu, A. Binzer-Panchal, C. Österholm, T. Del Peso Santos, L. Rabbani, HF. Asl, A. Skaftason, V. Ljungström, A. Lundholm, M. Koutroumani, Z. Haider, C. Jylhä, J. Mollstedt, L. Mansouri, K. Plevova, A....
Language English Country England, Great Britain
Document type Journal Article
NLK
ProQuest Central
from 2000-01-01 to 1 year ago
Open Access Digital Library
from 1997-01-01
Nursing & Allied Health Database (ProQuest)
from 2000-01-01 to 1 year ago
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
Public Health Database (ProQuest)
from 2000-01-01 to 1 year ago
- MeSH
- Alternative Splicing MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell * genetics pathology metabolism MeSH
- Phosphoproteins * genetics metabolism MeSH
- Humans MeSH
- Mutation * MeSH
- Bromodomain Containing Proteins MeSH
- Chromatin Assembly and Disassembly * MeSH
- RNA Splicing Factors * genetics metabolism MeSH
- Spliceosomes * metabolism genetics MeSH
- Transcription Factors genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
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.
Central European Institute of Technology Masaryk University Brno Czech Republic
Department of Biology School of Science National and Kapodistrian University of Athens Athens Greece
Department of Hematology Hospital Pitie Salpetriere Sorbonne University Paris France
Department of Immunology Erasmus MC University Medical Center Rotterdam Rotterdam Netherlands
Department of Immunology Mayo Clinic Rochester USA
Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden
Department of Oncology Pathology Science for Life Laboratory Karolinska Institutet Stockholm Sweden
Division of Experimental Oncology IRCCS Ospedale San Raffaele Milan Italy
Division of Hematology Department of Internal Medicine Mayo Clinic Rochester MN USA
Division of Hematology Department of Medicine Stanford University Medical Center Stanford CA USA
Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece
Institute of Applied Biosciences Centre for Research and Technology Hellas Thessaloniki Greece
References provided by Crossref.org
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- $a 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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