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.


RESULTS
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
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.
Dudley
Darryll D
DD
Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Wang
Hong-Cheng
HC
Sun
Xiao-Hong
XH
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D017931:DNA Primers; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000502:physiology*; D016399:Lymphoma, T-Cell / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D051880:Receptors, Notch / Q000502:physiology*; D000072056:Transcription Factor HES-1; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D018398:Homeodomain Proteins; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse
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