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Hematopoiesis and leukemogenesis in mice expressing oncogenic Nras(G12D) from the endogenous locus

  1. Author:
    Li, Q.
    Haigis, K. M.
    McDaniel, A.
    Harding-Theobald, E.
    Kogan, S. C.
    Akagi, K.
    Wong, J. C. Y.
    Braun, B. S.
    Wolff, L.
    Jacks, T.
    Shannon, K.

  2. Author Address

    [McDaniel, Andrew; Harding-Theobald, Emily; Wong, Jasmine C. Y.; Braun, Benjamin S.; Shannon, Kevin] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA. [Li, Qing] Univ Calif San Francisco, Dept Med, San Francisco, CA 94158 USA. [Haigis, Kevin M.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA. [Haigis, Kevin M.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. [Kogan, Scott C.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94158 USA. [Kogan, Scott C.; Shannon, Kevin] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA. [Akagi, Keiko] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol, Columbus, OH 43210 USA. [Akagi, Keiko] Ohio State Univ, Ctr Comprehens Canc, Dept Immunol, Columbus, OH 43210 USA. [Akagi, Keiko] Ohio State Univ, Ctr Comprehens Canc, Dept Med Genet, Columbus, OH 43210 USA. [Wolff, Linda] NCI, Cellular Oncol Lab, Frederick, MD 21701 USA. [Jacks, Tyler] MIT, Ctr Canc Res, Cambridge, MA 02139 USA. [Jacks, Tyler] MIT, Dept Biol, Cambridge, MA 02139 USA.;Shannon, K, Univ Calif San Francisco, Dept Pediat, Helen Diller Family Canc Res Bldg,1450 3rd St,Rm, San Francisco, CA 94158 USA.;shannonk@peds.ucsf.edu
    1. Year: 2011
    2. Date: Feb
  2. Journal: Blood
    1. 117
    2. 6
    3. Pages: 2022-2032
  4. Type of Article: Article
  5. ISSN: 0006-4971
  1. 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. (Blood. 2011; 117(6): 2022-2032)

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External Sources

  1. View Full Text
  2. DOI: 10.1182/blood-2010-04-280750
  3. View record in Web of Science®
  4. WOS: 000287192300039

Library Notes

  1. Fiscal Year: FY2010-2011
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