主催: 公益社団法人日本薬理学会
会議名: 第97回日本薬理学会年会
回次: 97
開催地: 神戸
開催日: 2023/12/14 - 2023/12/16
Hematopoietic stem cells (HSCs) proliferate and differentiate in response to stress; however, the mechanisms by which HSCs respond to stress and restore hematopoiesis remain unclear. High mobility group AT-hook 2 (Hmga2) is a chromatin modifier that is highly expressed in fetal HSCs and activates the transcription of stem cell signature genes. In the homeostatic state, hematopoiesis remained unchanged in Hmga2 knock-out mice and Hmga2-overexpressing conditional knock-in (KI) mice; however, in response to an injection with 5-fluorouracil (5-FU) that up-regulated the expression of TNF-a in bone marrow, the self-renewal of HSCs was enhanced in Hmga2 KI mice, whereas HSC and megakaryocyte progenitor cell numbers decreased in Hmga2 KO mice and hematopoietic recovery was delayed. Since the expression of Hmga2 was necessary and sufficient to repress the transcription of interferon stimulated genes and inflammatory response genes in HSCs after the 5-FU injection, Hmga2 bound to distinct regions and modulate chromatin accessibility in HSCs after the in vivo injection of 5-FU and the in vitro treatment with TNF-a. The acidic domain in the Hmga2 protein was phosphorylated by Casein kinase 2, which mediates TNF-a downstream signaling; therefore, the inhibition of Hmga2 phosphorylation impaired the stress-induced chromatin binding of Hmga2, the transcription of target genes, and the expansion of HSCs under stress conditions. This TNF-a-CK2-Hmga2 axis was critical for stress hematopoiesis and was also hijacked in human MDS stem/progenitor cells. Collectively, the present results revealed Hmga2-mediated mechanisms to remodel HSCs and highlight the important role of the TNF-a-CK2-Hmga2 axis under homeostatic and stress conditions.