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 death¹. 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 hosts². 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, O'Donnell 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.