TY - JOUR
T1 - Hematopoiesis and leukemogenesis in mice expressing oncogenic Nras G12D from the endogenous locus
AU - Li, Qing
AU - Haigis, Kevin M.
AU - McDaniel, Andrew
AU - Harding-Theobald, Emily
AU - Kogan, Scott C.
AU - Akagi, Keiko
AU - Wong, Jasmine C.Y.
AU - Braun, Benjamin S.
AU - Wolff, Linda
AU - Jacks, Tyler
AU - Shannon, Kevin
PY - 2011/2/10
Y1 - 2011/2/10
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2010-04-280750
DO - 10.1182/blood-2010-04-280750
M3 - Article
C2 - 21163920
AN - SCOPUS:79951472496
SN - 0006-4971
VL - 117
SP - 2022
EP - 2032
JO - Blood
JF - Blood
IS - 6
ER -