In:
Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. SCI-29-SCI-29
Abstract:
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. Disclosures No relevant conflicts of interest to declare.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V126.23.SCI-29.SCI-29
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2015
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
