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To examine the effects of Notch signaling on hematopoiesis, we transplanted mice with progenitors transduced with a constitutively active form of Notch1 (Notch1IC) or the Notch1 target genes Hes. Notch1IC-transduced cells induce T cell tumors and cannot generate B lymphocytes in vivo. Hes-transplanted mice remained healthy but cells transduced with Hes1 or Hes5 were partially impaired in their ability to differentiate into B cells. Both Hes1 and Hes5 were upregulated in the BM of Notch1IC mice and their ability to interfere with the transcriptional activity of E2A in a reporter assay was comparable to that of Notch1IC. This suggests that the inhibition of B cell development in the Notch1IC-transduced cells could be mediated by the interference of HES1/HES5 proteins with E2A. Hes1-, Hes5- and Notch1IC-transduced bone marrow cells cultured ex vivo in a colony forming assay in the presence of cytokines that promote myeloid differentiation remained very immature, indicating that the myeloid potential of these bone marrow cells was altered. Thymocytes overexpressing Hes1, Hes5 or Notch1IC matured normally into CD4 and CD8 single positive cells in vivo. Altogether our data suggest that Notch1IC induces T cell tumors independently of Hes genes but that its interference with lymphoid B and myeloid maturation is partly mediated by Hes1 and Hes5. DOI:

Sequence analysis of the human retinoblastoma gene cDNA revealed the presence of repeated elements in the form of direct repeats, inverted repeats and dyad symmetries. The clustering of the dyad symmetrical elements in some exons, #16 and #17, coincides with the hot spots for structural aberrations of the RB-1 locus previously observed in tumors. The RB-1 gene is divided into at least 27 exons distributed over 200 kbp. Three potential Sp1 binding sites are presented within 600 bp upstream of the translation start site. A DNA fragment containing these Sp1 sites ligated to a promotorless CAT gene can promote its transcription in transfected cell culture.