Tp53 and Tet2 mutations cooperatively transform progenitors (RNA-Seq)

Mutations and deletions in TP53 are associated with adverse outcome in patients with myeloid malignancies and developing improved therapies for TP53-mutant leukemias is of urgent need. Here we identify mutations in TET2 as the most commonly co-existing mutation in TP53 mutant acute myeloid leukemia (AML) patients. Combined hematopoietic-specific deletion of TET2 and TP53 in mice enhanced self-renewal compared to deletion of either gene alone. Tet2/Tp53 double knockout mice developed serially transplantable AML. Both mice as well as patients with AML and combined TET2/TP53 alterations upregulated innate immune signaling in malignant cells. Mice with TET2/TP53 loss had expansion of monocytic myeloid-derived suppressor cells which impaired T cell proliferation. Moreover, patients and mice with TP53/TET2 double mutant AML upregulated TIGIT ligands CD155 and CD112 on malignant cells. TIGIT blocking antibodies augmented the ability of NK cells to kill Tet2/Tp53 double mutant AML cells, reduced leukemic burden, and extended the survival of TET2/TP53 double knockout mice. These data thereby identify a previously unexplored link between TET2 and TP53 mutations and highlight therapeutic means to overcome the immunosuppressive bone marrow environment in this adverse subtype of AML. Overall design: To understand the molecular mechanisms underlying AML transformation upon combined mutation in TET2 and TP53, we performed bulk RNA-seq of Lin-cKIT+ myeloid progenitors (LK) and Lin-cKIT+Sca-1+ (LSK) cells from diseased Vav-cre Tet2fl/fl Tp53fl/fl mice developing AML and age-matched Vav-cre Tp53fl/fl, Vav-cre Tet2 fl/fl, and WT mice.