The Role of Receptor Interacting Protein Kinase in Myelopoiesis in Health and Disease

Ripk1 -/- mice die at birth from systemic inflammation and this was not transferable in hematopoietic reconstitution experiments. One caveat to interpreting this result is our observation that Ripk1 -/- progenitors failed to engraft lethally irradiated hosts properly. Competitive and serial transplantation experiments suggest that Ripk1 -/- hematopoietic stem and progenitor cells (HSPC) have a cell-intrinsic defect. Blocking TNF allowed Ripk1 -/- progenitors to reconstitute effectively supporting the idea that the cell-intrinsic defect is due to hyper-sensitivity to TNF induced death 1 . TNF can induce both caspase-8 dependent apoptosis and RIPK3/MLKL dependent necroptosis. These results prompted us to determine whether RIPK1 and TNF induced cell death had a role in leukemogenesis. We therefore generated mouse models of AML leukemia by retroviral infection of fusion MLL-ENL constructs into E14 fetal liver cells from Ripk1 -/- , Ripk3 -/- , Mlkl -/- , Casp8 -/- Ripk3 -/- , Casp8 -/- Mlkl -/- and Ripk3 -/- Mlkl -/- mice and transplanting them into sub-lethally irradiated wild type hosts 2 . Except for the Ripk1 -/- MLL-ENL there was no difference in the development of leukemia from these genotypes compared to MLL-ENL wild type. Surprisingly however, given the defective reconstitution potential of Ripk1 -/- HSPC, leukemia induced lethality occurred more than two times faster in Ripk1 -/- MLL-ENL (20 days) compared to wild type MLL-ENL (50 days). No differences in blood profile, histology, myeloid markers or cell cycling were observed. Even more surprisingly, when we retransplanted these leukemias, Ripk1 -/- MLL-ENL had a prolonged disease onset (over 80 days) compared to wild type (around 25 days). I will describe experiments to discover the mechanism behind these intriguing findings. 1. Rickard JA, O9Donnell JA, Evans JM, Lalaoui N, Poh AR, et al. RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis. Cell. 2014;157:1175-1188. 2. Zuber J, Radtke I, Pardee TS, Zhao Z, Rappaport AR, et al. Mouse models of human AML accurately predict chemotherapy response. Genes Dev. 2009;23:877-889. Disclosures No relevant conflicts of interest to declare.