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 Blood, 1 October 2007, Vol. 110, No. 7, pp. 2610-2619.
Prepublished online as a Blood First Edition Paper on May 16, 2007; DOI 10.1182/blood-2007-01-066209.

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NEOPLASIA

p16INK4A tumor suppressor gene expression and CD3{epsilon} deficiency but not pre-TCR deficiency inhibit TAL1-linked T-lineage leukemogenesis

Magali Fasseu1, Peter D. Aplan2, Martine Chopin1, Nicolas Boissel3, Jean-Christophe Bories4, Jean Soulier1, Harald von Boehmer5, François Sigaux1, and Armelle Regnault1

1 Institut National de la Santé et de la Recherche Médicale (INSERM) U462, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France; 2 Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; 3 INSERM U662, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France; 4 EA3963-Université Paris 7-Denis Diderot-INSERM, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France; 5 Dana-Farber Cancer Institute, Boston, MA

Inactivation of the CDKN2 genes that encode the p16INK4A and p14ARF proteins occurs in the majority of human T-cell acute lymphoblastic leukemias (T-ALLs). Ectopic expression of TAL1 and LMO1 genes is linked to the development of T-ALL in humans. In TAL1xLMO1 mice, leukemia develops in 100% of mice at 5 months. To identify the molecular events crucial to leukemic transformation, we produced several mouse models. We report here that expression of P16INK4A in developing TAL1xLMO1 thymocytes blocks leukemogenesis in the majority of the mice, and the leukemias that eventually develop show P16INK4A loss of expression. Events related to the T-cell receptor ß selection process are thought to be important for leukemic transformation. We show here that the absence of the pT{alpha} chain only slightly delays the appearance of TAL1xLMO1-induced T-ALL, which indicates a minor role of the pT{alpha} chain. We also show that the CD3{epsilon}-mediated signal transduction pathway is essential for this transformation process, since the TAL1xLMO1xCD3{epsilon}-deficient mice do not develop T-ALL for up to 1 year.


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