Resistance to cell death is one of the main problems in Acute Myeloid Leukemia (AML) contributing to treatment failure, disease relapse and a low 5-year survival rate (<30%). Thus, understanding cell death related genes function during the progression and treatment of the disease, is important for the development of more efficient therapies. Necroptosis is an alternative form of programmed cell death that occurs independent of caspase activity and could be exploited as an anti-cancer therapy to overcome apoptosis resistance. The receptor-interacting protein kinase 1 (RIPK1) is key effector of necroptosis, a regulator of apoptosis and inflammatory processes, and is essential for normal haematopoiesis. Mutations in RIPK1 have a significant impact in human health. Patients with RIPK1 deficiency present severe inflammation and immunodeficiency. In cancers, RIPK1 has been indicated as both tumor suppressor and promoter. In AML, loss of RIPK1 is correlated with unfavourable prognosis. Using murine models of AML that recapitulate human disease, we investigated the relevance of RIPK1 in AML development. Interestingly, loss of Ripk1 accelerated leukemogenesis driven by MLL translocations. RIPKI deficient leukaemias were characterised by rapid infiltration of blasts in the bone marrow, spleen and liver accompanied by high levels of granulocyte colony stimulating factor (G-CSF). Concurrently, intravital imaging revealed increased bone marrow infiltration of Ripk1-/- AMLs 10 days after transplant. Moreover, loss of G-CSF partially rescues the aggressive phenotype, suggesting a role for this cytokine in the progression of MLL driven AML. Together our results indicate tumor suppressor role for RIPK1 signalling in AML, providing new therapeutic opportunities for these leukaemias.
