If the Kras coding sequence is replaced by Hras, the embryonic lethality is rescued but adult animals develop dilated cardiomyopathy and elevated blood pressure, suggesting a unique role of KRAS in cardiovascular homeostasis. Homozygous Nras KO mice are overall Pazopanib healthy, but present impaired antiviral immune response and T-cell function due to a reduced population of CD8+ cells in the thymus. After influenza virus infection, Nras KO mice showed a reduced response of CD4+ T lymphocytes, granulocytes, NK cells, macrophages, and CD8+ T lymphocytes. Notably the overall levels of RAS proteins in Nras KO mice remain unchanged due to a compensatory increase of KRAS and HRAS, suggesting a specific role for NRAS in lymphoid cells. The role of elevated RAS in cancer has been investigated in several mouse models. Myeloid malignancies with incomplete penetrance and long latency periods were observed when the bone marrow of irradiated mice was repopulated with cells overexpressing a constitutively active NRAS protein. Several animals presented increased numbers of granulocytes at the expense of lymphocytes, but due to the long latency and low penetrance, it was suggested that a secondary hit is required to induce cancer. However, when NRASG12D was expressed in early hematopoietic cells from an MSCV retroviral vector, myeloid disorders resembling human AML and CMML were efficiently induced by higher and lower NRAS signaling levels respectively. Heterozygous expression of NRASG12D fromthe endogenousNras locus in epiblast cells results in embryonic lethality. Heterozygous expression onlyinliver, spleenand bonemarrow resultsinamild phenotype dependent on genetic background and characterized by a wide spectrum of hematologic diseases. However, upon infection with the MOL4070LTR retrovirus, these animals developed AML considerably faster than control mice. Homozygous expression leads to myeloid hyperplasia with shorter latency. In semisolid culture, the bone marrow cells displayed an abnormal growth pattern, and after co-transplantation with competitor wild type cells into irradiated recipient mice, a dose-dependent phenotype was observed. Almost all animals with heterozygous expression of NrasG12D developed a CMML-like disease starting after 6 months. The mice suffered from anemia and developed myeloid hyperplasia in bone marrow and spleen. Homozygous expression did not induce sustained CMML but resulted in acute T-cell lymphoblastic leukemia/lymphoma. Increment of the number of transplanted cells changed the disease pattern of the recipient mice, as lethal myeloproliferative disease was induced in the majority of the mice independent on the number of NrasG12D alleles. Incidences resembling human B- and T-cell lymphoblastic leukemia/lymphoma were likewise observed but only upon transplantation of NrasG12D/G12D cells. Despitethe examples of overexpression ofwtNrasin human cancer and the large number of disease mouse models with deregulated Nras expression, onlytransgenic mice overexpressing wildtypeNras under the mouse mammary tumor virus long terminal repeat are earlier described. These developed hyperplasias and malignant tumors in the tissues with the highest transgene expression. We have recently developed a set of mouse models in which the murine leukemia virus Akv 1–99 long terminal repeat was introduced within the Nras locus at the exact positions of previously identified retroviralintegrations. Here we report on the early post natal pathology which is the consequence of an upregulated wt Nras expression from its endogenous locus, which is particularly increased in spleen.