The reported lethal phenotype has a complete penetrance within 3 weeks after birth, which indicates that the lethal condition does not require additional genetic events. With the aim to investigate the Foretinib effect of deregulation of wt Nras, we have recently created several knock-in mouse models in which a murine leukemia virus Akv 1–99 LTR was inserted at different positions within the Nras locus. In each mouse line, a single LTR was introduced at the exact position of previously identified retroviral insertions With the aim to investigate the effect of deregulation of wt Nras, we have recently created several knock-in mouse models in which a murine leukemia virus Akv 1–99 LTR was inserted at different positions within the Nras locus. In each mouse line, a single LTR was introduced at the exact position of previously identified retroviral insertions known to result in B-cell lymphomas. The mice suffered from significant weight loss and presented elevated levels of Tlymphocytes and myeloid cells within the spleen. This organ was reduced in the affected animals indicating altered cell proliferation, differentiation or survival. Furthermore, we found an increase of myeloid cells in thymus and blood, and an upregulation of Gcsf and Gfi1 mRNA in spleen which likely contributes to the increase of myeloid cells. On the basis of flow cytometry and histology, we refer to this as granulocytosis. This is the fastest lethal phenotype likely caused solely by upregulation of wt Nras. The early lethality precludes the detection of a possible effect on lymphomagenesis of the inserted LTR as might have been expected form the underlying insertional mutagenesis study. Transgenic mice with overexpression of wt Nras from a heterologouos promoter were previously reported to develope malignant tumors within one to a few months. The constitutive overexpression of Nras in our model limits the possibility to directly compare the results to earlier studies on the effect of expression of mutated Nras in adult bone marrow cells. However the observation of an intermediate phenotype in heterozygous mice shows that the cellular expansion of T-cells and myeloid cells is dose dependent as reported earlier. The early and uniform onset of the disease makes it very unlikely that a second event is required, even under the assumption that the Nras expression is already increased during embryonic development. However, because Notch1 mutations are frequently associated with T-cell malignancies, we checked homozygous mice for the most frequent Notch1 mutations and deletions in thymus of NrasLTR9S/LTR9S mice but found none. The absence of Notch1 alterations supports the conclusion that the increase of Nras expression is the primary cause of the observed lethal phenotype. A correlation between constitutively active NRAS and myeloid cells has been described in several mouse models,,, and T-cell upregulation upon increased NRAS expression is consistent with the T-cell reduction found in the Nras KO mouse model as well as the induced acute T-cell lymphoblastic leukemia/ lymphoma in the NrasG12D/G12D bone marrow transplantation model. Mutations causing constitutively active versions of RAS are often found in cancer and are likewise often used in transgenic mice and cell lines. In contrast, our model uses wild type Nras from the endogenous locus, and the NRAS protein still depends on physiological activation for its downstream signaling. The tissue distribution of the physiological activators may determine the final outcome of RAS signaling, since different activators of RAS might signal through specific downstream pathways.