Abstract B14: Hematopoietic RIPK1 deficiency results in bone marrow failure due to apoptosis and RIPK3-mediated necroptosis.

Abstract

Abstract The serine/threonine kinase RIPK1 is recruited to the TNF receptor 1 to mediate pro-inflammatory signaling and to regulate TNF-induced apoptosis and necroptosis. The kinase activity of RIPK1 is required for RIPK3 activation and induction of necroptosis, an inflammatory form of cell death. Although Ripk3-/- mice are viable, a RIPK1 deficiency results in postnatal lethality. To identify the lineages and cell types that depend on RIPK1 for survival, we generated conditional Ripk1 mice. Tamoxifen administration to adult RosaCreERT2Ripk1fl/fl mice results in lethality due to cell death in the intestinal and hematopoietic lineages. Similarly, Ripk1 deletion in cells of the hematopoietic lineage stimulates pro-inflammatory cytokine and chemokine production and hematopoietic cell death, resulting in bone marrow failure. The cell death reflects cell intrinsic survival roles for RIPK1 in hematopoietic stem and progenitor cells, as Vav-iCre Ripk1fl/fl fetal liver cells failed to reconstitute hematopoiesis in lethally irradiated recipients. We demonstrate that a RIPK3 deficiency partially rescues hematopoiesis in Vav-iCre Ripk1fl/fl mice, revealing that RIPK1 mediates survival by preventing RIPK3-mediated necroptosis. However, Vav-iCre Ripk1fl/fl Ripk3-/- progenitors remain TNF sensitive in vitro and fail to repopulate irradiated mice. These genetic studies reveal that a hematopoietic RIPK1 deficiency triggers both apoptotic and necroptotic death that is partially prevented by a RIPK3 deficiency. Thus, in contrast to in vitro studies, RIPK1 functions in hematopoietic cells to negatively regulate RIPK3 and prevent inflammation. Citation Format: Justine R. Roderick, Nicole C. Hermance, Matija Zelic, Apostolos Polykratis, Manolis Pasparakis, Michelle A. Kelliher. Hematopoietic RIPK1 deficiency results in bone marrow failure due to apoptosis and RIPK3-mediated necroptosis. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B14.