JMJD3 mediated senescence is required to overcome stress induced hematopoietic defects

Cellular senescence in stem cells compromises regenerative capacity, promotes chronic inflammation, and is implicated in aging. Hematopoietic stem and progenitor cells (HSPCs) are responsible for producing mature blood cells, however, how cellular senescence influences their function is largely unknown. Here, we show that JMJD3, a histone demethylase, activates cellular senescence via p16 ^Ink4a upregulation in competition with Polycomb group proteins, and reprograms HSPC integrity to overcome hematopoietic defects induced by replicative and oncogenic stresses. JMJD3 deficiency impaired stem cell potential, proper cell cycle regulation, and WNT pathway activation in HSPCs under stress conditions. These impaired phenotypes were rescued through exogenous and retroviral introduction of p16 ^Ink4a . This JMJD3-p16 ^INK4a axis in hematopoiesis is age-dependent and is distinct from cellular senescence. Treatment with a JMJD3 selective inhibitor attenuated leukemic potential during cellular senescence. Taken together, these results demonstrate that JMJD3-p16 ^INK4a mediates cellular senescence and plays critical roles in the functional integrity of HSPCs under stress conditions, suggesting a new link for aging and anti-cancer therapies.