The non-canonical BAF chromatin remodeling complex is a novel target of spliceosome dysregulation in SF3B1-mutated chronic lymphocytic leukemia

Leukemia. 2024 Nov;38(11):2429-2442. doi: 10.1038/s41375-024-02379-4.

Daniel Hägerstrand ^# ¹, Blaž Oder ^# ¹, Diego Cortese ¹, Ying Qu ¹, Amrei Binzer-Panchal ¹, Cecilia Österholm ¹, Teresa Del Peso Santos ¹, Leily Rabbani ¹, Hassan Foroughi Asl ¹, Aron Skaftason ¹, Viktor Ljungström ², August Lundholm ¹, Maria Koutroumani ³, Zahra Haider ¹, Cecilia Jylhä ¹ ⁴, John Mollstedt ¹, Larry Mansouri ¹, Karla Plevova ⁵ ⁶ ⁷, Andreas Agathangelidis ³ ⁸, Lydia Scarfò ⁹ ¹⁰, Marine Armand ¹¹, Alice F Muggen ¹², Neil E Kay ¹³ ¹⁴, Tait Shanafelt ¹⁵, Davide Rossi ¹⁶, Lukas M Orre ¹⁷, Sarka Pospisilova ⁵ ⁶ ⁷, Konstantin Barylyuk ¹⁷, Frederic Davi ¹¹, Mattias Vesterlund ¹⁷, Anton W Langerak ¹², Janne Lehtiö ¹⁷, Paolo Ghia ⁹ ¹⁰, Kostas Stamatopoulos ¹ ³ ¹⁸, Lesley-Ann Sutton ¹, Richard Rosenquist ¹⁹ ²⁰

Affiliations

1 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
3 Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece.
4 Clinical Genetics and Genomics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.
5 Department of Internal Medicine - Hematology and Oncology, Medical Faculty, Masaryk University and University Hospital Brno, Brno, Czech Republic.
6 Institute of Medical Genetics and Genomics, Medical Faculty, Masaryk University and University Hospital Brno, Brno, Czech Republic.
7 Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
8 Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece.
9 Università Vita-Salute San Raffaele, Milan, Italy.
10 Division of Experimental Oncology, IRCCS, Ospedale San Raffaele, Milan, Italy.
11 Department of Hematology, Hospital Pitie-Salpetriere, Sorbonne University, Paris, France.
12 Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
13 Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
14 Department of Immunology, Mayo Clinic, Rochester, USA.
15 Division of Hematology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA.
16 Department of Hematology, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland.
17 Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
18 Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
19 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. richard.rosenquist@ki.se.
20 Clinical Genetics and Genomics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden. richard.rosenquist@ki.se.
# Contributed equally.

PMID: 39261602 DOI: 10.1038/s41375-024-02379-4

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 SF3B1^MUT and 17 SF3B1^WT 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 SF3B1^K700E 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 SF3B1^MUT 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 SF3B1^MUT CLL.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-103632

PROTAC BRD9 Degrader-1

PROTAC BRD9 Degrader

PROTACs; Epigenetic Reader Domain

Cancer

Name
Email *

	Sorry, but the email address you supplied was invalid.