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¹ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
² Department of Medicine, University of Chicago, Chicago, IL 60637
³ Department of Microbiology-Immunology, Northwestern University, Chicago, IL 60611

CORRESPONDENCE Harald von Boehmer: harald_von_boehmer{at}dfci.harvard.edu

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)-β⁺ 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-β^– cells that give rise to monoclonal tumors with a single, unique TCR-β chain and diverse TCR- chains, pinpointing malignant transformation to a stage after pre-TCR signaling and before completion of TCR- 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.

© 2008 Li et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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