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Cancer-associated SF3B1-K700E mutation controls immune responses by regulating Treg function via aberrant Anapc13 splicing

ABSTRACT: Recurrent somatic mutations in spliceosome factor 3b subunit 1 (SF3B1) are identified in hematopoietic cell-derived malignancies, with SF3B1-K700E being the most common one. Here we show that Treg specific expression of SF3B1-K700E (Sf3b1K700Efl/+/Foxp3YFP-Cre) results in spontaneous autoimmune phenotypes including enlarged spleen and tissue infiltration with IFN-γ-producing CD4+ T cells. 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 insertion a 231 bp DNA fragment to the 5’ untranslated region (UTR). Forced expression of Anapc13 gene restores the differentiation and ability of Sf3b1K700Efl/+/Foxp3YFP-Cre Tregs to prevent adoptive transfer colitis. Our results thus highlight the impact of a hematological malignancy-associated SF3B1 mutation on immune responses and indicate a potential relationship between splicing factor mutation-dysregulated immune responses and cancer development.

ORGANISM(S): Mus musculus

PROVIDER: GSE267436 | GEO | 2024/06/01

REPOSITORIES: GEO

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Cancer-associated SF3B1-K700E mutation controls immune responses by regulating Treg function via aberrant Anapc13 splicing

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