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 malignancies, with SF3B1-K700E being the most common one. Here, we show that regulatory T cell (T_reg)-specific expression of SF3B1-K700E (Sf3b1^K700Efl/+/Foxp3^YFP-Cre) results in spontaneous autoimmune phenotypes. CD4⁺ T cells from Sf3b1^K700Efl/+/Foxp3^YFP-Cre mice display defective T_reg differentiation and inhibitory function, which is demonstrated by failed prevention of adoptive transfer colitis by Sf3b1^K700Efl/+/Foxp3^YFP-Cre T_regs. 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 Sf3b1^K700Efl/+/Foxp3^YFP-Cre T_regs to prevent adoptive transfer colitis. In addition, acute myeloid leukemia grows faster in aged, but not young, Sf3b1^K700Efl/+/Foxp3^YFP-Cre mice compared to Foxp3^YFP-Cre mice. Our results highlight the impact of cancer-associated SF3B1 mutation on immune responses, which affect cancer development.