Cancer-associated SF3B1-K700E mutation controls immune responses by regulating T _reg function via aberrant <i>Anapc13</i> 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 (<i>Sf3b1^K700Efl/+/Foxp3^YFP-Cre</i>) results in spontaneous autoimmune phenotypes. CD4⁺ T cells from <i>Sf3b1^K700Efl/+/Foxp3^YFP-Cre</i> mice display defective T_reg differentiation and inhibitory function, which is demonstrated by failed prevention of adoptive transfer colitis by <i>Sf3b1^K700Efl/+/Foxp3^YFP-Cre</i> T_regs. Mechanically, SF3B1-K700E induces an aberrant splicing event that results in reduced expression of a cell proliferation regulator <i>Anapc13</i> due to the insertion of a 231-base pair DNA fragment to the 5' untranslated region. Forced expression of the <i>Anapc13</i> gene restores the differentiation and ability of <i>Sf3b1^K700Efl/+/Foxp3^YFP-Cre</i> T_regs to prevent adoptive transfer colitis. In addition, acute myeloid leukemia grows faster in aged, but not young, <i>Sf3b1^K700Efl/+/Foxp3^YFP-Cre</i> mice compared to <i>Foxp3^YFP-Cre</i> mice. Our results highlight the impact of cancer-associated <i>SF3B1</i> mutation on immune responses, which affect cancer development.