TET2 and MSH6: A Novel Role for MMR in the Pathogenesis of Myeloid Malignancies

TET2 mutations (TET2 MT) occur in up to 40% of myeloid neoplasms and increase linearly with age. That these lesions are founding hits can be concluded from clonal architecture and from the presence of subclinical TET2 MT clones in healthy individuals at risk for subsequent MDS. Though TET2 MT are heterogeneous, most disrupt TET2 catalytic domain dioxygenase activity; these widespread LOF mutations implicate TET2 as a bona fide tumor-suppressor gene (TSG). As downstream targets have not been identified as being associated with TET2 MT, the precise mechanisms of TET2 MT in leukemogenesis remains unclear. We studied whether TET2 MT predispose cells to acquiring additional oncogenic mutations through faulty DNA repair to produce clonally acquired mutator phenotypes.