Aspp1 Preserves Hematopoietic Stem Cell Pool Integrity and Prevents Malignant Transformation

Quiescent hematopoietic stem cells (HSCs) are prone to mutagenesis, and accumulation of mutations can result in hematological malignancies. The mechanisms through which HSCs prevent such detrimental accumulation, however, are unclear. Here, we show that Aspp1 coordinates with p53 to maintain the genomic integrity of the HSC pool. Aspp1 is preferentially expressed in HSCs and restricts HSC pool size by attenuating self-renewal under steady-state conditions. After genotoxic stress, Aspp1 promotes HSC cycling and induces p53-dependent apoptosis in cells with persistent DNA damage foci. Beyond these p53-dependent functions, Aspp1 attenuates HSC self-renewal and accumulation of DNA damage in p53 null HSCs. Consequently, concomitant loss of Aspp1 and p53 leads to the development of hematological malignancies, especially T cell leukemia and lymphoma. Together, these data highlight coordination between Aspp1 and p53 in regulating HSC self-renewal and DNA damage tolerance and suggest that HSCs possess specific mechanisms that prevent accumulation of mutations and malignant transformation.