TY - JOUR
T1 - Alternative Promoter Usage at the Notch1 Locus Supports Ligand-Independent Signaling in T Cell Development and Leukemogenesis
AU - Gomez-del Arco, Pablo
AU - Kashiwagi, Mariko
AU - Jackson, Audrey F.
AU - Naito, Taku
AU - Zhang, Jiangwen
AU - Liu, Feifei
AU - Kee, Barbara
AU - Vooijs, Marc
AU - Radtke, Freddy
AU - Miguel Redondo, Juan
AU - Georgopoulos, Katia
PY - 2010/11/24
Y1 - 2010/11/24
N2 - 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-independent Notch1 isoforms were required for Ikaros-mediated leukemogenesis. Notch1 alternative-promoter usage was observed during T cell development and T-ALL progression. Thus, a network of epigenetic and transcriptional regulators controls conventional and unconventional Notch signaling during normal development and leukemogenesis.
AB - 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-independent Notch1 isoforms were required for Ikaros-mediated leukemogenesis. Notch1 alternative-promoter usage was observed during T cell development and T-ALL progression. Thus, a network of epigenetic and transcriptional regulators controls conventional and unconventional Notch signaling during normal development and leukemogenesis.
U2 - 10.1016/j.immuni.2010.11.008
DO - 10.1016/j.immuni.2010.11.008
M3 - Article
C2 - 21093322
SN - 1074-7613
VL - 33
SP - 685
EP - 698
JO - Immunity
JF - Immunity
IS - 5
ER -