Loss of DEK induces radioresistance of murine restricted hematopoietic progenitors

Abstract

Self-renewing hematopoietic stem cells and multipotent progenitor cells are responsible for maintaining hematopoiesis throughout an individual's lifetime. For overall health and survival, it is critical that the genome stability of these cells is maintained and that the cell population is not exhausted. Previous reports have indicated that the DEK protein, a chromatin structural protein that functions in numerous nuclear processes, is required for DNA damage repair in vitro and long-term engraftment of hematopoietic stem cells in vivo. Therefore, we investigated the role of DEK in normal hematopoiesis and response to DNA damaging agents in vivo. Here, we report that hematopoiesis is largely unperturbed in DEK knockout mice compared with wild-type (WT) controls. However, DEK knockout mice have fewer radioprotective units, but increased capacity to survive repeated sublethal doses of radiation exposure compared with WT mice. Furthermore, this increased survival correlated with a sustained quiescent state in which DEK knockout restricted hematopoietic progenitor cells (HPC-1) were nearly three times more likely to be quiescent following irradiation compared with WT cells and were significantly more radioresistant during the early phases of myeloid reconstitution. Together, our studies indicate that DEK functions in the normal hematopoietic stress response to recurrent radiation exposure.