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 Baking Powder 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 tool 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.