Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus
Autor: | Andrew S. McDaniel, Tyler Jacks, Linda Wolff, Emily Harding-Theobald, Jasmine C. Wong, Qing Li, Keiko Akagi, Kevin M. Haigis, Benjamin S. Braun, Kevin Shannon, Scott C. Kogan |
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Rok vydání: | 2011 |
Předmět: |
Neuroblastoma RAS viral oncogene homolog
Myeloid Immunology Gene Expression Mice Transgenic Biology medicine.disease_cause Biochemistry Mice Myeloproliferative Disorders medicine Animals Humans Erythropoiesis Lymphopoiesis Progenitor cell Myelopoiesis Myeloid Neoplasia Myeloid leukemia Cell Biology Hematology Hematopoietic Stem Cells Mice Mutant Strains Hematopoiesis Mice Inbred C57BL Leukemia Myeloid Acute Haematopoiesis Genes ras medicine.anatomical_structure Amino Acid Substitution Mutation ras Proteins Cancer research Cytokines KRAS |
Zdroj: | Blood. 117:2022-2032 |
ISSN: | 1528-0020 0006-4971 |
Popis: | 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-NrasG12D 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-KrasG12D 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. |
Databáze: | OpenAIRE |
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