Oncogenic activation of the Notch1 gene by deletion of its promoter in Ikaros-deficient T-ALL.

Abstract

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 γ-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.

• Authors: Robin Jeannet, Jérôme Mastio, Alejandra Macias-Garcia, Attila Oravecz, Todd Ashworth, Anne-Solen Geimer Le Lay, Bernard Jost, Stéphanie Le Gras, Jacques Ghysdael, Thomas Gridley, Tasuku Honjo, Freddy Radtke, Jon C Aster, Susan Chan, Philippe Kastner
• Journal: Blood (Blood) Vol. 116 Issue 25 Pg. 5443-54 (Dec 16 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20829372 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Immunoglobulin J Recombination Signal Sequence-Binding Protein
• Notch1 protein, mouse
• Notch3 protein, mouse
• RNA, Messenger
• Rbpj protein, mouse
• Receptor, Notch1
• Receptor, Notch3
• Receptors, Notch
• Zfpn1a1 protein, mouse
• Ikaros Transcription Factor

Topics

• Animals
• Blotting, Northern
• Blotting, Western
• Cell Transformation, Neoplastic
• DNA Primers (chemistry, genetics)
• Flow Cytometry
• Gene Expression Regulation, Neoplastic
• Ikaros Transcription Factor (physiology)
• Immunoglobulin J Recombination Signal Sequence-Binding Protein (physiology)
• Mice
• Mice, Knockout
• Mutation (genetics)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism, pathology)
• Promoter Regions, Genetic (genetics)
• RNA, Messenger (genetics)
• Receptor, Notch1 (genetics)
• Receptor, Notch3
• Receptors, Notch (physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Sequence Deletion
• Survival Rate
• Transcriptional Activation (physiology)