LAUSR

High mobility group AT-hook 2 (Hmga2) is a chromatin modifier protein that plays a critical role in fetal development and leukemia propagation by binding to chromatin and DNA via its AT-hook domains. However, the molecular mechanisms by which Hmga2 activates the expression of target genes to drive the self-renewal of hematopoietic stem cells (HSCs) remain unclear. We generated Rosa26 locus Hmga2 conditional knock-in mice and found that overexpression of Hmga2 promoted self-renewal of normal HSCs, but maintained their fitness in bone marrow, and consequently was not sufficient to initiate malignancy. This result is consistent with previous findings showing that Hmga2 is a proto-oncogene. We also assessed the cellular functions of Hmga2 mutants lacking functional domains and demonstrated that the C-terminus acidic domain of Hmga2 and the domain’s linker region were critical for activating genes involved in stem cell signatures, such as the Igf2bp2 gene, to drive proliferation of HSCs. In contrast, overexpression of Hmga1, a member of the Hmga family with a different linker region, did not drive proliferation of HSCs. Our results reveal a critical role for the acidic domain of Hmga2 and the domain’s linker region in modulating the transcription and self-renewal functions of HSCs.