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

Qing Li, Kevin M. Haigis, Andrew McDaniel, Emily Harding-Theobald, Scott C. Kogan, Keiko Akagi, Jasmine C.Y. Wong, Benjamin S. Braun, Linda Wolff, Tyler Jacks, Kevin Shannon

Research output: Contribution to journalArticle

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Abstract

NRAS is frequently mutated in hematologic malignancies. We generated Mx1-Cre, Lox-STOP-Lox (LSL)-NrasG12D 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-NrasG12D 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-NrasG12D 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 KrasG12D expression results in markedly elevated Ras protein expression and Ras-GTP levels in Mac1 + cells, whereas Mx1-Cre, LSL-NrasG12D 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.

Original languageEnglish (US)
Pages (from-to)2022-2032
Number of pages11
JournalBlood
Volume117
Issue number6
DOIs
StatePublished - Feb 10 2011

Fingerprint

ras Proteins
Hematopoiesis
Guanosine Triphosphate
Myeloproliferative Disorders
Hematopoietic Stem Cells
Intercellular Signaling Peptides and Proteins
Genes
Cells
Tissue
Cytokines
Testing
Hematologic Neoplasms
Tissue Distribution
Retroviridae
Acute Myeloid Leukemia
Leukemia
Phenotype
Population
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Li, Q., Haigis, K. M., McDaniel, A., Harding-Theobald, E., Kogan, S. C., Akagi, K., ... Shannon, K. (2011). Hematopoiesis and leukemogenesis in mice expressing oncogenic Nras G12D from the endogenous locus. Blood, 117(6), 2022-2032. https://doi.org/10.1182/blood-2010-04-280750

Hematopoiesis and leukemogenesis in mice expressing oncogenic Nras G12D from the endogenous locus. / Li, Qing; Haigis, Kevin M.; McDaniel, Andrew; Harding-Theobald, Emily; Kogan, Scott C.; Akagi, Keiko; Wong, Jasmine C.Y.; Braun, Benjamin S.; Wolff, Linda; Jacks, Tyler; Shannon, Kevin.

In: Blood, Vol. 117, No. 6, 10.02.2011, p. 2022-2032.

Research output: Contribution to journalArticle

Li, Q, Haigis, KM, McDaniel, A, Harding-Theobald, E, Kogan, SC, Akagi, K, Wong, JCY, Braun, BS, Wolff, L, Jacks, T & Shannon, K 2011, 'Hematopoiesis and leukemogenesis in mice expressing oncogenic Nras G12D from the endogenous locus', Blood, vol. 117, no. 6, pp. 2022-2032. https://doi.org/10.1182/blood-2010-04-280750
Li, Qing ; Haigis, Kevin M. ; McDaniel, Andrew ; Harding-Theobald, Emily ; Kogan, Scott C. ; Akagi, Keiko ; Wong, Jasmine C.Y. ; Braun, Benjamin S. ; Wolff, Linda ; Jacks, Tyler ; Shannon, Kevin. / Hematopoiesis and leukemogenesis in mice expressing oncogenic Nras G12D from the endogenous locus. In: Blood. 2011 ; Vol. 117, No. 6. pp. 2022-2032.
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