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Ripk3 signaling regulates the number and function of HSCs during stress and represses radiation-induced leukemia in mice

ABSTRACT: We found that Ripk3 signaling selectively regulates both the number and function of hematopoietic stem cells (HSCs) during stress conditions and inhibits ionizing radiation (IR)-induced leukemia development in mice. During serial transplantation, which stimulates a chronic Ripk3 activation in HSCs, Ripk3 promotes the loss of HSCs via Mlkl-mediated necroptosis and impairs HSC function by inducing ROS-p38-p16 mediated senescence. In response to 6Gy of IR, which induces the activation of p53-p21-mediated cell cycle arrest/senescence in HSCs, Ripk3 is required for the activation of NF-κB and permits the survival of the senescent cells. However, in response to multiple low doses of IR (1.75 × 4), Ripk3 signaling inhibits leukemia development by inducing ROS-p38-p16-mediated senescence and repressing Ire1α-Xbp1-Dnajb8 UPR fitness in pre-leukemic stem cells (pre-LSCs) and also inducing Mlkl-dependent clearance of pre-LSCs. Mlkl deletion prevents IR-induced loss of HSCs and slightly accelerates leukemia development in mice, while Ripk3 deletion represses both necroptotic and senescence signals in pre-LSCs and significantly accelerates IR-induced leukemia development. Our study suggests that immediately after high dose IR, temporal inhibition of Ripk3-NF-κB signaling might help to prevent long-term residual damage (LT-RDs) in bone marrow by eliminating the IR-induced senescent HSCs. However, in response to low dose radiation, induced activation of Ripk3 signaling at the pre-leukemia stage might help to prevent the accumulation of mutant HSCs and the development of leukemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE139143 | GEO | 2022/06/29

REPOSITORIES: GEO

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