Necroptosis of a Small Subset of Hematopoietic Progenitors Induces Autoimmune Bone Marrow Failure

Abstract

Acquired aplastic anemia (AAA) is an autoimmune-mediated bone marrow failure (BMF) syndrome. Cryptic clonal genetic lesions were commonly detected in a small subset of hematopoietic stem/progenitor cells (HSPCs) in most patients' BM samples. The mechanism by which the autoimmune reaction is initiated is unknown. Whether and how these cryptic clonal genetic lesions might cause autoimmune BMF have not yet been determined. We found that mice with spontaneous deletion of the TGFβ-activated kinase-1 (Tak1) gene in a small subset of HSPCs (1-3%) developed BMF which resembled the clinical manifestations of AAA patients. BMF in such mice could be reversed by depletion of CD4+ T lymphocytes or treatment with IFN-γ, suggesting a Th1 cell-mediated autoimmune mechanism. Interestingly, the disease onset and progression of BMF in such mice were significantly accelerated by inactivation of TNF-α signaling, indicating that TNF-α might restrict the progression of autoimmune BMF. Furthermore, we determined that the necroptosis of a small subset of hematopoietic cells is the cause of autoimmune BMF because such BMF can be completely prevented by deletion of Rip3, a key necroptotic mediator. Our study suggested that the necroptosis of a small subset of hematopoietic cells induces autoimmune BMF, and that elevated TNF-α restricts the progression of such autoimmune BMF. We believe that, in addition to inhibiting T-cell-mediated autoimmune reactions to induce disease remission, repression of the necroptosis of mutant HSPCs might be necessary to prevent disease relapse and progression of autoimmune BM failure. DisclosuresStiff:Gilead: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Fate Therapeutics: Research Funding; Plasmacyclics: Consultancy, Honoraria, Research Funding; Eisai: Research Funding.