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Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus. | LitMetric

AI Article Synopsis

  • NRAS mutations are common in blood cancers, and researchers created a specific mouse model (Mx1-Cre, LSL-Nras(G12D)) to study the effects of this mutation in hematopoietic (blood-forming) cells.
  • These mice develop a mild myeloproliferative disorder but later succumb to various types of blood cancers, with notable differences in how their blood stem cells respond to growth factors compared to other models (like Kras mutations).
  • The findings suggest that this mouse model can be used to explore the unique characteristics of different Ras mutations, identify genetic partners involved in cancer, and assess potential new treatments.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056645PMC
http://dx.doi.org/10.1182/blood-2010-04-280750DOI Listing

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