Gadd45a regulates hematopoietic stem cell stress responses in mice.
نویسندگان
چکیده
Gadd45a has been involved in DNA damage response and in many malignancies, including leukemia. However, the function of Gadd45a in hematopoietic stem cells (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 reconstitution ability in serial transplantation. Following ionizing radiation (IR), young Gadd45a(-/-) HSCs exhibited an increased resistance to IR-induced DNA damage, associated with a decrease in the apoptosis rate and delayed DNA repair. The significantly higher level of DNA damage in Gadd45a(-/-) 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.
منابع مشابه
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 h...
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ورودعنوان ژورنال:
- Blood
دوره 123 6 شماره
صفحات -
تاریخ انتشار 2014