Oncogenic K-ras in mouse models of myeloproliferative disease and acute myeloid leukemia.
Oncogenic N-RAS and K-RAS mutations are among the most frequently detected genetic alterations in patients with acute myeloid leukemia (AML). Recently, the role of oncogenic K-ras in leukemogenesis was investigated in a novel mouse model utilizing interferon (IFN)-inducible, Cre-mediated expression of oncogenic K-ras from its endogenous promoter. Conditional expression of oncogenic K-ras from its endogenous promoter in the hematopoietic system induces a lethal myeloproliferative disease in mice, but not AML, indicating that additional mutations are required for AML development. These results are consistent with a model in which the AML phenotype requires at least two cooperating mutations in the hematopoietic progenitor cells: one promoting proliferation and enhanced cell survival (such as oncogenic ras or a constitutively activated receptor tyrosine kinase) and one associated with impaired differentiation and enhanced immortalization (such as loss-of-function mutations in hematopoietic transcription factors). The model system with oncogenic K-ras provides a versatile platform to test the contribution of cooperating mutations in AML, and the efficacy of Ras pathway inhibitors in vivo.
Chan
Iris T
IT
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. iris_chan@dfci.harvard.edu
Gilliland
D Gary
DG
D000818:Animals; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D018631:ras Proteins