TET2-Mutated Clonal Hematopoiesis is Dependent on DOT1L Activity and Thrombopoietin Receptor Signaling

Ten-Eleven Translocation-2 (TET2) mutations drive clonal hematopoiesis (CH), a condition associated with increased risk of hematologic malignancies and other age-related inflammatory illnesses. Here, we performed an epigenetic drug screen and found that inhibition of disruptor of telomeric silencing 1-like (DOT1L), a H3K79 methyltransferase, selectively reduced the expansion of Tet2 knockout (Tet2KO) hematopoietic stem and progenitor cells (HSPCs) over Tet2 wild-type (Tet2WT) HSPCs. This mutation-specific dependency was observed at the level of hematopoietic stem cells (HSCs) through single cell RNA-sequencing analysis and was found to be mediated through increased H3K79 dimethylation at the Mpl locus and enhanced expression of Mpl, which encodes the thrombopoietin receptor (TPO-R). Inhibition of TPO-R expression or its downstream signaling was sufficient to suppress the expansion of murine and human TET2-deficient HSPCs. Our findings demonstrate that DOT1L and TPO-R signaling are required for the clonal expansion of TET2-deficient HSPCs, thus uncovering potential therapeutic strategies against TET2-mutated CH.