Oncogenesis of T-ALL and Nonmalignant Consequences of Overexpressing Intracellular NOTCH1

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Oncogenesis of T-ALL and Nonmalignant Consequences of Overexpressing Intracellular NOTCH1

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Title: Oncogenesis of T-ALL and Nonmalignant Consequences of Overexpressing Intracellular NOTCH1
Author: Gounari, Fotini; Khazaie, Khashayarsha; Li, Xiaoyu; Protopopov, Alexei; von Boehmer, Harald

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Citation: Li, Xiaoyu, Fotini Gounari, Alexei Protopopov, Khashayarsha Khazaie, and Harald von Boehmer. 2008. Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1. Journal of Experimental Medicine 205(12): 2851-2861.
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Abstract: Mutations resulting in overexpression of intracellular Notch1 (ICN1) are frequently observed in human T cell acute lymphoblastic leukemia (T-ALL). We have determined the consequences of ICN1 overexpression from retroviral vectors introduced into bone marrow cells. Early consequences are the generation of polyclonal nontumorigenic \(CD4^+8^+\) T cell receptor (TCR)-\(\alpha \beta^+\) cells that do not qualify as tumor precursors despite the observation that they overexpress Notch 1 and c-Myc and degrade the tumor suppressor E2A by posttranslational modification. The first tumorigenic cells are detected among more immature \(CD4^−8^+TCR-\alpha \beta^-\) cells that give rise to monoclonal tumors with a single, unique TCR-\(\beta\) chain and diverse TCR-\(\alpha\) chains, pinpointing malignant transformation to a stage after pre-TCR signaling and before completion of TCR-\(\alpha\) rearrangement. In T-ALL, E2A deficiency is accompanied by further transcriptional up-regulation of c-Myc and concomitant dysregulation of the c-Myc-p53 axis at the transcriptional level. Even though the tumors consist of phenotypically heterogeneous cells, no evidence for tumor stem cells was found. As judged by array-based comparative genomic hybridization (array CGH) and spectral karyotype (SKY) analysis, none of the tumors arise because of genomic instability.
Published Version: doi: 10.1084/jem.20081561
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585834/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10212565
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