title: Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus.
abstract: NRAS is frequently mutated in hematologic malignancies. We generated Mx1-Cre, Lox-STOP-Lox (LSL)-Nras(G12D) mice to comprehensively analyze the phenotypic, cellular, and biochemical consequences of endogenous oncogenic Nras expression in hematopoietic cells. Here we show that Mx1-Cre, LSL-Nras(G12D) mice develop an indolent myeloproliferative disorder but ultimately die of a diverse spectrum of hematologic cancers. Expressing mutant Nras in hematopoietic tissues alters the distribution of hematopoietic stem and progenitor cell populations, and Nras mutant progenitors show distinct responses to cytokine growth factors. Injecting Mx1-Cre, LSL-Nras(G12D) mice with the MOL4070LTR retrovirus causes acute myeloid leukemia that faithfully recapitulates many aspects of human NRAS-associated leukemias, including cooperation with deregulated Evi1 expression. The disease phenotype in Mx1-Cre, LSL-Nras(G12D) mice is attenuated compared with Mx1-Cre, LSL-Kras(G12D) mice, which die of aggressive myeloproliferative disorder by 4 months of age. We found that endogenous Kras(G12D) expression results in markedly elevated Ras protein expression and Ras-GTP levels in Mac1(+) cells, whereas Mx1-Cre, LSL-Nras(G12D) mice show much lower Ras protein and Ras-GTP levels. Together, these studies establish a robust and tractable system for interrogating the differential properties of oncogenic Ras proteins in primary cells, for identifying candidate cooperating genes, and for testing novel therapeutic strategies.
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, CA 94158-9001, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
authors.forename: Andrew
authors.initials: A
authors.lastname: McDaniel
authors.forename: Emily
authors.initials: E
authors.lastname: Harding-Theobald
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.forename: Jasmine C Y
authors.initials: JC
authors.lastname: Wong
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Braun
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004920:Erythropoiesis / Q000235:genetics; D015870:Gene Expression; D011905:Genes, ras; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D038042:Myelopoiesis / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D018631:ras Proteins