title: Nras overexpression results in granulocytosis, T-cell expansion and early lethality in mice.
abstract: NRAS is a proto-oncogene involved in numerous myeloid malignancies. Here, we report on a mouse line bearing a single retroviral long terminal repeat inserted into Nras. This genetic modification resulted in an increased level of wild type Nras mRNA giving the possibility of studying the function and activation of wild type NRAS. Flow cytometry was used to show a variable but significant increase of immature myeloid cells in spleen and thymus, and of T-cells in the spleen. At an age of one week, homozygous mice began to retard compared to their wild type and heterozygous littermates. Two weeks after birth, animals started to progressively lose weight and die before weaning. Heterozygous mice showed a moderate increase of T-cells and granulocytes but survived to adulthood and were fertile. In homozygous and heterozygous mice Gfi1 and Gcsf mRNA levels were upregulated, possibly explaining the increment in immature myeloid cells detected in these mice. The short latency period indicates that Nras overexpression alone is sufficient to cause dose-dependent granulocytosis and T-cell expansion.
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Louise Berkhoudt
authors.initials: LB
authors.lastname: Lassen
authors.forename: Borja
authors.initials: B
authors.lastname: Ballarín-González
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmitz
authors.forename: Annette
authors.initials: A
authors.lastname: Füchtbauer
authors.forename: Finn Skou
authors.initials: FS
authors.lastname: Pedersen
authors.forename: Ernst-Martin
authors.initials: EM
authors.lastname: Füchtbauer
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation; D005804:Genes, Lethal; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006720:Homozygote; D007964:Leukocytosis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D020837:SOS1 Protein / Q000235:genetics; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D060168:Thymocytes / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D015431:Weight Loss / Q000235:genetics; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse; D020837:SOS1 Protein; D014157:Transcription Factors; D020663:ras Guanine Nucleotide Exchange Factors; D016179:Granulocyte Colony-Stimulating Factor; D016283:Proto-Oncogene Proteins p21(ras)