Cancer-associated SF3B1-K700E mutation controls immune responses by regulating Treg function via aberrant Anapc13 splicing.
Sci Adv
; 10(38): eado4274, 2024 Sep 20.
Article
in En
| MEDLINE
| ID: mdl-39303038
ABSTRACT
Recurrent somatic mutations in spliceosome factor 3b subunit 1 (SF3B1) are identified in hematopoietic malignancies, with SF3B1-K700E being the most common one. Here, we show that regulatory T cell (Treg)-specific expression of SF3B1-K700E (Sf3b1K700Efl/+/Foxp3YFP-Cre) results in spontaneous autoimmune phenotypes. CD4+ T cells from Sf3b1K700Efl/+/Foxp3YFP-Cre mice display defective Treg differentiation and inhibitory function, which is demonstrated by failed prevention of adoptive transfer colitis by Sf3b1K700Efl/+/Foxp3YFP-Cre Tregs. Mechanically, SF3B1-K700E induces an aberrant splicing event that results in reduced expression of a cell proliferation regulator Anapc13 due to the insertion of a 231-base pair DNA fragment to the 5' untranslated region. Forced expression of the Anapc13 gene restores the differentiation and ability of Sf3b1K700Efl/+/Foxp3YFP-Cre Tregs to prevent adoptive transfer colitis. In addition, acute myeloid leukemia grows faster in aged, but not young, Sf3b1K700Efl/+/Foxp3YFP-Cre mice compared to Foxp3YFP-Cre mice. Our results highlight the impact of cancer-associated SF3B1 mutation on immune responses, which affect cancer development.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
T-Lymphocytes, Regulatory
/
RNA Splicing Factors
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Mutation
Limits:
Animals
/
Humans
Language:
En
Journal:
Sci Adv
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: