Journal
BLOOD
Volume 116, Issue 25, Pages 5443-5454Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-05-286658
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Funding
- Institut National du Cancer (INCa)
- La Ligue Contre le Cancer
- Agence Nationale de la Recherche
- Association pour la Recherche sur le Cancer
- Fondation de France
- Inserm
- CNRS
- l'Universite de Strasbourg
- La Ligue Regionale Contre le Cancer
- Ministere de la Recherche et de la Technologie (MRT)
- La Ligue Nationale Contre le Cancer
- Conacyt Association of Mexico
- Fondation pour la Recherche Medicale
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The Notch pathway is frequently activated in T-cell acute lymphoblastic leukemias (T-ALLs). Of the Notch receptors, Notch1 is a recurrent target of gain-of-function mutations and Notch3 is expressed in all T-ALLs, but it is currently unclear how these receptors contribute to T-cell transformation in vivo. We investigated the role of Notch1 and Notch3 in T-ALL progression by a genetic approach, in mice bearing a knockdown mutation in the Ikaros gene that spontaneously develop Notch-dependent T-ALL. While deletion of Notch3 has little effect, T cell-specific deletion of floxed Notch1 promoter/exon 1 sequences significantly accelerates leukemogenesis. Notch1-deleted tumors lack surface Notch1 but express gamma-secretase-cleaved intracellular Notch1 proteins. In addition, these tumors accumulate high levels of truncated Notch1 transcripts that are caused by aberrant transcription from cryptic initiation sites in the 3' part of the gene. Deletion of the floxed sequences directly reprograms the Notch1 locus to begin transcription from these 3' promoters and is accompanied by an epigenetic reorganization of the Notch1 locus that is consistent with transcriptional activation. Further, spontaneous deletion of 5' Notch1 sequences occurs in approximately 75% of Ikaros-deficient T-ALLs. These results reveal a novel mechanism for the oncogenic activation of the Notch1 gene after deletion of its main promoter. (Blood. 2010; 116(25): 5443-5454)
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