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p16INK4A tumor suppressor gene expression and CD3ϵ deficiency but not pre-TCR deficiency inhibit TAL1-linked T-lineage leukemogenesis

2007; Elsevier BV; Volume: 110; Issue: 7 Linguagem: Inglês

10.1182/blood-2007-01-066209

1528-0020

Magali Fasseu, Peter D. Aplan, Martine Chopin, Nicolas Boissel, Raphaël Borie, Jean Soulier, Harald von Boehmer, François Sigaux, Armelle Régnault,

Renal and related cancers

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 β selection process are thought to be important for leukemic transformation. We show here that the absence of the pTα chain only slightly delays the appearance of TAL1xLMO1-induced T-ALL, which indicates a minor role of the pTα chain. We also show that the CD3ϵ-mediated signal transduction pathway is essential for this transformation process, since the TAL1xLMO1xCD3ϵ-deficient mice do not develop T-ALL for up to 1 year.