Alternative promoter usage at the Notch1 locus supports ligand-independent signaling in T cell development and leukemogenesis.

ABSTRACT: Loss of the transcription factor Ikaros is correlated with Notch receptor activation in T cell acute lymphoblastic leukemia (T-ALL). However, the mechanism remains unknown. We identified promoters in Notch1 that drove the expression of Notch1 proteins in the absence of a ligand. Ikaros bound to both canonical and alternative Notch1 promoters and its loss increased permissive chromatin, facilitating recruitment of transcription regulators. At early stages of leukemogenesis, increased basal expression from the canonical and 5'-alternative promoters initiated a feedback loop, augmenting Notch1 signaling. Ikaros also repressed intragenic promoters for ligand-independent Notch1 proteins that are cryptic in wild-type cells, poised in preleukemic cells, and active in leukemic cells. Only ligand-i

SUBMITTER: Gomez-del Arco P 

PROVIDER: S-EPMC3072037 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature