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

Varování

Publikace nespadá pod Filozofickou fakultu, ale pod Lékařskou fakultu. Oficiální stránka publikace je na webu muni.cz.

Autoři	HAGERSTRAND Daniel ODER Blaz CORTESE Diego QU Ying BINZER-PANCHAL Amrei OSTERHOLM Cecilia SANTOS Teresa Del Peso RABBANI Leily ASL Hassan Foroughi SKAFTASON Aron LJUNGSTROM Viktor LUNDHOLM August KOUTROUMANI Maria HAIDER Zahra JYLHA Cecilia MOLLSTEDT John MANSOURI Larry PLEVOVÁ Karla AGATHANGELIDIS Andreas SCARFO Lydia ARMAND Marine MUGGEN Alice F KAY Neil E SHANAFELT Tait ROSSI Davide ORRE Lukas M POSPÍŠILOVÁ Šárka BARYLYUK Konstantin DAVI Frederic VESTERLUND Mattias LANGERAK Anton W LEHTIO Janne GHIA Paolo STAMATOPOULOS Kostas SUTTON Lesley-Ann ROSENQUIST Richard
Rok publikování	2024
Druh	Článek v odborném periodiku
Časopis / Zdroj	Leukemia
Fakulta / Pracoviště MU	Lékařská fakulta
Citace
www	https://www.nature.com/articles/s41375-024-02379-4
Doi	http://dx.doi.org/10.1038/s41375-024-02379-4
Klíčová slova	SF3B1 mutation; Chronic lymphocytic leukemia; Chromatin remodeling complex; Spliceosome dysregulation; Non-canonical BAF complex
Přiložené soubory	The_non-canonical_BAF_chromatin_remodeling_complex_is_a_novel_target_of_spliceosome_dysregulation_in_SF3B1-mutated_chronic_lymphocytic_leukemia.pdf
Popis	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.
Související projekty:	Pokročilé sekvenační metody pro analýzu strukturních přestaveb nádorového genomu Národní ústav pro výzkum rakoviny