Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice

Ataxia telangiectasia mutated (ATM) kinase plays an essential role in the maintenance of genomic stability. ATM-deficient (ATM(−/−)) mice exhibit hematopoietic stem cell (HSC) dysfunction and a high incidence of lymphoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM(−/−) HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM(−/−) mice. Instead, ATM and Gadd45a double knockout (ATM(−/−) Gadd45a(−/−)) HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM(−/−) HSCs in HSC transplantation experiments. Further experiments revealed that the aggravated defect of ATM(−/−) Gadd45a(−/−) HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signaling pathway. Additionally, ATM(−/−) Gadd45a(−/−) mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM(−/−) mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which subsequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM(−/−) HSCs.