title: MEK1 is required for the development of NRAS-driven leukemia.
abstract: The dual-specificity kinases MEK1 and MEK2 act downstream of RAS/RAF to induce ERK activation, which is generally considered protumorigenic. Activating MEK mutations have not been discovered in leukemia, in which pathway activation is caused by mutations in upstream components such as RAS or Flt3. The anti-leukemic potential of MEK inhibitors is being tested in clinical trials; however, downregulation of MEK1 promotes Eμ-Myc-driven lymphomagenesis and MEK1 ablation induces myeloproliferative disease in mice, raising the concern that MEK inhibitors may be inefficient or counterproductive in this context. We investigated the role of MEK1 in the proliferation of human leukemic cell lines and in retroviral models of leukemia. Our data show that MEK1 suppression via RNA interference and genomic engineering does not affect the proliferation of human leukemic cell lines in culture; similarly, MEK1 ablation does not impact the development of MYC-driven leukemia in vivo. In contrast, MEK1 ablation significantly reduces tumorigenesis driven by Nras alone or in combination with Myc. Thus, while MEK1 restricts proliferation and tumorigenesis in some cellular and genetic contexts, it cannot be considered a tumor suppressor in the context of leukemogenesis. On the contrary, its role in NRAS-driven leukemogenesis advocates the use of MEK inhibitors, particularly in combination with PI3K/AKT inhibitors, in hematopoietic malignancies involving RAS activation.
authors.affiliation: Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Joanna D
authors.initials: JD
authors.lastname: Nowacka
authors.affiliation: Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Baumgartner
authors.affiliation: Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.|Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, A. Meyer Children's Hospital-University of Florence, Florence, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Pelorosso
authors.affiliation: Research Institute of Molecular Pathology, Vienna, Austria.
authors.forename: Mareike
authors.initials: M
authors.lastname: Roth
authors.affiliation: Research Institute of Molecular Pathology, Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Manuela
authors.initials: M
authors.lastname: Baccarini
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D020558:GTP Phosphohydrolases / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D000074084:THP-1 Cells; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: C489427:MYC protein, human; D008565:Membrane Proteins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: MEK1; MYC; NRAS; leukemia