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Höckendorf, Ulrike; Yabal, Monica; Herold, Tobias; Munkhbaatar, Enkhtsetseg; Rott, Stephanie; Jilg, Stefanie; Kauschinger, Johanna; Magnani, Giovanni; Reisinger, Florian; Heuser, Michael; Kreipe, Hans; Sotlar, Karl; Engleitner, Thomas; Rad, Roland; Weichert, Wilko; Peschel, Christian; Ruland, Jürgen; Heikenwalder, Mathias; Spiekermann, Karsten; Slotta-Huspenina, Julia; Groß, Olaf; Jost, Philipp J. (2016): RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells. In: Cancer Cell, Vol. 30, No. 1: pp. 75-91
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Since acute myeloid leukemia (AML) is characterized by the blockade of hematopoietic differentiation and cell death, we interrogated RIPK3 signaling in AML development. Genetic loss of Ripk3 converted murine FLT3-ITD-driven myeloproliferation into an overt AML by enhancing the accumulation of leukemia-initiating cells (LIC). Failed inflammasome activation and cell death mediated by tumor necrosis factor receptor caused this accumulation of LIC exemplified by accelerated leukemia onset in Il1r1(-/-), Pycard(-/-), and Tnfr1/2(-/-) mice. RIPK3 signaling was partly mediated by mixed lineage kinase domain-like. This link between suppression of RIPK3, failed interleukin-1 beta release, and blocked cell death was supported by significantly reduced RIPK3 in primary AML patient cohorts. Our data identify RIPK3 and the inflammasome as key tumor suppressors in AML.