Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1
Open Access
- 3 November 2008
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 205 (12), 2851-2861
- https://doi.org/10.1084/jem.20081561
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)-αβ+ 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-αβ− cells that give rise to monoclonal tumors with a single, unique TCR-β chain and diverse TCR-α chains, pinpointing malignant transformation to a stage after pre-TCR signaling and before completion of TCR-α 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.This publication has 39 references indexed in Scilit:
- FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitorsThe Journal of Experimental Medicine, 2007
- The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemiaThe Journal of Experimental Medicine, 2007
- Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancersNature, 2007
- NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growthProceedings of the National Academy of Sciences of the United States of America, 2006
- c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphomaGenes & Development, 2006
- E proteins and Notch signaling cooperate to promote T cell lineage specification and commitmentThe Journal of Experimental Medicine, 2006
- Transcriptional networks in developing and mature B cellsNature Reviews Immunology, 2005
- Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic LeukemiaScience, 2004
- Notch Signaling: Cell Fate Control and Signal Integration in DevelopmentScience, 1999
- Frequent provirus insertional mutagenesis of Notch1 in thymomas of MMTVD/myc transgenic mice suggests a collaboration of c-myc and Notch1 for oncogenesis.Journal of Bone and Joint Surgery, 1996