ArticleBlood2010
Oncogenic activation of the Notch1 gene by deletion of its promoter in Ikaros-deficient T-ALL.
Article in Blood, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 79 citations in OpenAlex.
- Trial
- Genetic susceptibility ofGlobal medical genetics · 2025Article
- The IKAROS Transcription Factor Gene IKZF1 as a Critical Regulator in the Pathogenesis of Childhood Acute Lymphoblastic Leukemia: Insights from a Bangladeshi Population.Indian journal of clinical biochemistry : IJCB · 2025Article
- Expression status transition ofF1000Research · 2025Article
- Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.Signal transduction and targeted therapy · 2024Review
- Role of epigenetic in cancer biology, in hematologic malignancies and in anticancer therapy.Frontiers in molecular medicine · 2024Review
- IKAROS Family Transcription Factors in Lymphocyte Differentiation and Function.Advances in experimental medicine and biology · 2024Review
- Article
- A double-negative thymocyte-specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and β-selection.Nature immunology · 2022Article
- Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 inFrontiers in immunology · 2022Article
- E Protein Transcription Factors as Suppressors of T Lymphocyte Acute Lymphoblastic Leukemia.Frontiers in immunology · 2022Review
- IKAROS is required for the measured response of NOTCH target genes upon external NOTCH signaling.PLoS genetics · 2021Article
- Morphologic and Immunohistochemical Characterization of Spontaneous Lymphoma/Leukemia in NSG Mice.Veterinary pathology · 2020Article
- Convergent genetic aberrations in murine and human T lineage acute lymphoblastic leukemias.PLoS genetics · 2019Article
- Article
- A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia.Cancer cell · 2017Article
- High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia.Blood · 2016Article
- PRDM14 promotes RAG-dependent Notch1 driver mutations in mouse T-ALL.Biology open · 2016Article
- The molecular pathogenesis of chronic lymphocytic leukaemia.Nature reviews. Cancer · 2016Review
- Off-Target V(D)J Recombination Drives Lymphomagenesis and Is Escalated by Loss of the Rag2 C Terminus.Cell reports · 2015Article
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Authors and funding
15 authors at 6 institutions in 4 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.