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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5463-5472.
Prepublished online as a Blood First Edition Paper on February 22, 2007; DOI 10.1182/blood-2006-11-059071.
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NEOPLASIA
ß-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation
Zhuyan Guo1,
Marei Dose1,
Damian Kovalovsky1,
Rui Chang1,
Jennifer O'Neil2,
A. Thomas Look2,
Harald von Boehmer2,
Khashayarsha Khazaie2,3, and
Fotini Gounari1
1 Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston;
2 Dana-Farber Cancer Institute, Harvard Medical School, Boston;
3 Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
Activation of ß-catenin has been causatively linked to the etiology of colon cancer. Conditional stabilization of this molecule in pro-T cells promotes thymocyte development without the requirement for pre-TCR signaling. We show here that activated ß-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. ß-Catenin–induced thymic lymphomas have a leukemic arrest at the early DP stage. Lymphomagenesis requires Rag activity, which peaks at this developmental stage, as well as additional secondary genetic events. A consistent secondary event is the transcriptional up-regulation of c-Myc, whose activity is required for transformation because its conditional ablation abrogates lymphomagenesis. In contrast, the expression of Notch receptors as well as targets is reduced in DP thymocytes with stabilized ß-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in ß-catenin–induced lymphomas. Thus, ß-catenin activation may provide a mechanism for the induction of T-cell–acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation.
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