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Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and
bone marrow failure in mice.
Wagner PN, Shi Q, Salisbury-Ruf CT, Zou J, Savona MR, Fedoriw Y, Zinkel SS
Submitted Externally on 2/22/2019
Volume : Pages
133 : 107 - 120
Hematopoiesis is a dynamic system that requires balanced cell division,
differentiation, and death. The 2 major modes of programmed cell death,
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 proapoptotic Bcl-2 family members Bax and Bak
inhibits bone marrow apoptosis. Further deletion of the BH3-only member Bid (to
generate VavCreBaxBakBid triple-knockout [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 and culminating in bone marrow failure.
Genetically restoring Ripk1 to wild-type levels restores peripheral red cell
counts as well as normal cytokine production. TKO bone marrow is hypercellular
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.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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