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Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice

Patrice N. Wagner, Qiong Shi, Christi T. Salisbury-Ruf, Jing Zou, Michael R. Savona, Yuri Fedoriw and Sandra S. Zinkel

Key points

  • Unrestrained bone marrow necroptosis promotes inflammatory cytokine production that impairs HSPC function.

  • A new role for a recognized pro-apoptotic protein in programmed cell death fate linking hematopoietic necroptosis to bone marrow failure.

Abstract

Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The two major modes of programmed cell death (PCD), apoptosis and necroptosis, share molecular machinery, but diverge in outcome with important implications for the microenvironment: apoptotic cells are removed in an immune silent process, whereas necroptotic cells leak cellular contents that incite inflammation. Given the importance of cytokine directed cues for hematopoietic cell survival and differentiation, the impact on hematopoietic homeostasis of biasing cell death fate to necroptosis is substantial and poorly understood. Here we present a mouse model with increased bone marrow necroptosis. Deletion of the pro-apoptotic Bcl-2 family members Bax and Bak inhibits bone marrow apoptosis. Further deletion of the BH3-only member Bid, to generate VavCreBaxBakBid TKO mice, leads to unrestrained bone marrow necroptosis driven by increased Rip1 kinase (Ripk1). TKO mice display loss of progenitor cells leading to increased cytokine production and increased stem cell proliferation and exhaustion, culminating in bone marrow failure (BMF). Genetically restoring Ripk1 to wild type levels restores peripheral red cell counts as well as normal cytokine production. TKO bone marrow is hyper cellular with abnormal differentiation, resembling the human disorder Myelodysplastic syndrome (MDS), and we demonstrate increased necroptosis in MDS bone marrow. Finally, we show that Bid impacts necroptotic signaling through modulation of Caspase-8-mediated Ripk1 degradation. Thus we demonstrate that dysregulated necroptosis in hematopoiesis promotes bone marrow progenitor cell death that incites inflammation, impairs hematopoietic stem cells, and recapitulates the salient features of the bone marrow failure disorder, MDS.

  • Submitted May 17, 2018.
  • Accepted October 24, 2018.