title: RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells.
abstract: 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-1β 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.
authors.affiliation: III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Höckendorf
authors.affiliation: III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Monica
authors.initials: M
authors.lastname: Yabal
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), 81377 München, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Herold
authors.affiliation: III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Enkhtsetseg
authors.initials: E
authors.lastname: Munkhbaatar
authors.affiliation: III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rott
authors.affiliation: III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jilg
authors.affiliation: III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kauschinger
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Magnani
authors.affiliation: Institute of Virology, Helmholtz Zentrum München für Gesundheit und Umwelt (HMGU), 85764 Neuherberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Reisinger
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.affiliation: Institute of Pathology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.affiliation: Institute of Pathology, Ludwig-Maximilians-University (LMU), 80337 München, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Sotlar
authors.affiliation: II. Medical Department for Gastroentreology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Engleitner
authors.affiliation: II. Medical Department for Gastroentreology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Rad
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: Institute of Virology, Helmholtz Zentrum München für Gesundheit und Umwelt (HMGU), 85764 Neuherberg, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), 81377 München, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.affiliation: Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Slotta-Huspenina
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Groß
authors.affiliation: III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: philipp.jost@tum.de.
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Jost
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D015536:Down-Regulation; D020869:Gene Expression Profiling / Q000379:methods; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009374:Neoplasms, Experimental; D014411:Neoplastic Stem Cells / Q000166:cytology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D058847:Inflammasomes; D018124:Receptors, Tumor Necrosis Factor; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse