The TET protein family interactor PROSER1 sustains hematopoietic stem cell function

Ten-eleven translocation (TET) enzymes are epigenetic regulators important for the prevention of hematological malignancies. Proline and serine rich 1 (PROSER1), a known TET protein interactor, has a critical role in modulating TET-mediated DNA demethylation during development. However, the potential involvement of PROSER1 in the regulation of hematopoiesis and leukemogenesis remains unknown. Here, we demonstrate that the leukemia-suppressive functions of TET2 are preserved in the absence of PROSER1. Nonetheless, we find that loss of PROSER1 partially recapitulates the aberrant enhancer DNA methylation phenotype observed upon TET2 knockout, suggesting that PROSER1 and TET2 play both cooperative and distinct roles in the regulation of DNA methylation in hematopoiesis. Importantly, using serial hematopoietic stem cell (HSC) transplantation assays, we find progressive exhaustion of HSC activity and reduction in hematopoietic lineage output upon loss of PROSER1. Our findings imply that, beyond the established role of TET2 loss-of-function mutations in promoting HSC expansion and leukemic transformation, accurate TET activity, regulated by PROSER1, is equally important to prevent HSC exhaustion and sustain normal hematopoiesis.