E2f coordinates the cell cycle and cell fate of hematopoietic progenitors to drive stress myelopoiesis
Viatour, P.; Cachon, A.; Crosier, G.; Kim, E.; Hayer, K.; Narravula, Y.; Hino, L.; Kjelstrom, S.; Tober, J.; Tan, K.; Speck, N. A.
Show abstract
During inflammation, cytokines such as Tnf, Il1{beta} and Il6 stimulate hematopoietic stem and progenitor cells (HSPCs) to proliferate and accelerate the production of inflammatory cells from the myeloid lineage through a process called stress myelopoiesis. Genetic inactivation of repressors of cell cycle activity in HSPCs is sufficient to recapitulate stress myelopoiesis, suggesting that the cell cycle activity and cell fate decision of proliferative HSPCs are coordinated by a cell intrinsic mechanism. However, the nature of this mechanism remains unknown. Here, we show that E2f simultaneously regulates proliferation of HSPCs, repression of alternative cell fates via the activation of Suz12/Ezh2-containing PRC2 complex and promotion of the myeloid fate by enhancing the signaling activity of CD131, the common {beta}chain receptor for {beta}cytokines (i.e. Il3 and Gm-Csf). Accordingly, dual inhibition of Ezh2 and {beta}cytokine signaling activity in a preclinical model of colitis represses stress myelopoiesis and restores colon homeostasis. Our results suggest that dual targeting of {beta}cytokine signaling and Ezh2 activity represents a novel therapeutic strategy to repress the production of pro-inflammatory myeloid cells in a wide spectrum of inflammatory diseases.
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