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