HEMATOPOIESIS AND STEM CELLS Gadd45a regulates hematopoietic stem cell stress responses in mice

• Loss of Gadd45a enhances HSC reconstitution on hematopoietic stress. • Gadd45a regulates DNA damage responses in HSCs. Gadd45a has been involved in DNA damage response and in many malignancies, including leukemia.However, the functionofGadd45a inhematopoietic stemcells (HSCs) remains unknown. Here, we reported that Gadd45a-deficient (Gadd45a) mice showed a normal hematologic phenotype under homeostatic conditions. However, following 5-fluorouracil treatment, Gadd45a HSCs exhibited a faster recovery, associated with an increase in the proliferation rate. Interestingly, young Gadd45a HSCs showed enhanced reconstitutionability in serial transplantation.Following ionizing radiation (IR), young Gadd45a HSCs exhibited an increased resistance to IR-induced DNA damage, associatedwith a decrease in the apoptosis rate and delayedDNA repair. The significantly higher level of DNAdamage inGadd45a HSCs ultimately promoted B-cell leukemia in further transplanted recipient mice. In old mice, Gadd45a HSCs were functionally equal to wild-type HSCs but exhibited more DNA damage accumulation and increased sensitivity to IR than wild-type HSCs. In conclusion, Gadd45a plays a significant role in HSC stress responses. Gadd45a deficiency leads to DNA damage accumulation and impairment in apoptosis after exposure to IR, which increases the susceptibility of leukemogenesis. (Blood. 2014;123(6):851-862)