Hes1 Potentiates T Cell Lymphomagenesis by Up-Regulating a Subset of Notch Target Genes

BACKGROUND: Hairy/Enhancer of Split (Hes) proteins are targets of the Notch signaling pathway and make up a class of basic helix-loop-helix (bHLH) proteins that function to repress transcription. Data from Hes1 deficient mice suggested that Hes1, like Notch1, is necessary for the progression of early T cell progenitors. Constitutive activation of Notch is known to cause T cell leukemia or lymphoma but whether Hes1 has any oncogenic activity is not known. METHODOLOGY/PRINCIPAL FINDINGS: We generated mice carrying a Hes1 transgene under control of the proximal promote of the lck gene. Hes1 expression led to a reduction in numbers of total thymocytes, concomitant with the increased percentage and number of immature CD8(+) (ISP) T cells and sustained CD25 expression in CD4(+)CD8(+) double positive (DP) thymocytes. Hes1 transgenic mice develop thymic lymphomas at about 20 weeks of age with a low penetrance. However, expression of Hes1 significantly shortens the latency of T cell lymphoma developed in Id1 transgenic mice, where the function of bHLH E proteins is inhibited. Interestingly, Hes1 increased expression of a subset of Notch target genes in pre-malignant ISP and DP thymocytes, which include Notch1, Notch3 and c-myc, thus suggesting a possible mechanism for lymphomagenesis. CONCLUSIONS/SIGNIFICANCE: We have demonstrated for the first time that Hes1 potentiates T cell lymphomagenesis, by up-regulating a subset of Notch target genes and by causing an accumulation of ISP thymocytes particularly vulnerable to oncogenic transformation.