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

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.