title: A MEK inhibitor abrogates myeloproliferative disease in Kras mutant mice.
abstract: Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are aggressive myeloproliferative neoplasms that are incurable with conventional chemotherapy. Mutations that deregulate Ras signaling play a central pathogenic role in both disorders, and Mx1-Cre, Kras(LSL-G12D) mice that express the Kras oncogene develop a fatal disease that closely mimics these two leukemias in humans. Activated Ras controls multiple downstream effectors, but the specific pathways that mediate the leukemogenic effects of hyperactive Ras are unknown. We used PD0325901, a highly selective pharmacological inhibitor of mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK), a downstream component of the Ras signaling network, to address how deregulated Raf/MEK/ERK (extracellular signal-regulated kinase) signaling drives neoplasia in Mx1-Cre, Kras(LSL-G12D) mice. PD0325901 treatment induced a rapid and sustained reduction in leukocyte counts, enhanced erythropoiesis, prolonged mouse survival, and corrected the aberrant proliferation and differentiation of bone marrow progenitor cells. These responses were due to direct effects of PD0325901 on Kras mutant cells rather than to stimulation of normal hematopoietic cell proliferation. Consistent with the in vivo response, inhibition of MEK reversed the cytokine hypersensitivity characteristic of Kras(G12D) hematopoietic progenitor cells in vitro. Our data demonstrate that deregulated Raf/MEK/ERK signaling is integral to the growth of Kras-mediated myeloproliferative neoplasms and further suggest that MEK inhibition could be a useful way to ameliorate functional hematologic abnormalities in patients with CMML and JMML.
authors: Department of Pediatrics, University of California, San Francisco, CA 94158, USA.
authors: Natalya
authors: N
authors: Lyubynska
authors: Matthew F
authors: MF
authors: Gorman
authors: Jennifer O
authors: JO
authors: Lauchle
authors: Wan Xing
authors: WX
authors: Hong
authors: Jon K
authors: JK
authors: Akutagawa
authors: Kevin
authors: K
authors: Shannon
authors: Benjamin S
authors: BS
authors: Braun
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D064547:Myxovirus Resistance Proteins; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D011993:Recombinant Fusion Proteins; C506614:mirdametinib; D004159:Diphenylamine; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)