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The MTCP1 oncogene modifies T-cell homeostasis before leukemogenesis in transgenic mice

Leukemia volume 21, pages 362–366 (2007)Cite this article

T-cell prolymphocytic leukemia (T-PLL) is a malignant hemopathy with a mature T-cell phenotype. It occurs in elderly people and is characterized by an aggressive tumoral syndrome with lymphocytosis, lymphadenopathy, hepatosplenomegaly and skin lesions. The prognosis is poor, with a median survival of approximately 9 months. Prolymphocytes are larger than lymphocytes and have a high nucleocytoplasmic ratio, a basophilic cytoplasm devoid of granules and a single prominent nucleus. The immunophenotype is that of post-thymic T lymphocytes, mainly CD4+CD8− (60%), CD4+CD8+ (25%) or rarely CD4−CD8+.1 The characterization of recurrent chromosomal aberrations associated with T-PLL allowed the identification of a novel oncogene family: the MTCP1/TCL1 family.2, 3 The juxtaposition of these genes to the TCRα or TCRβ loci, presumably during the V(D)J recombination, results in an increase in their expression in the T-cell lineage. The prevailing view of the MTCP1/TCL1 protein function is their primary involvement in the AKT signal-transduction pathway. However, the mechanism by which MTCP1/TCL1 proteins augment AKT activity remains incompletely resolved. The oncogenic properties of MTCP1 and TCL1 were demonstrated in animal models. Transgenic mice overexpressing MTCP1 or TCL1 in their T-cell lineage developed clonal proliferation of mature CD8+ T-cells resembling the human T-PLL.4, 5

Cellular behavior changes were then investigated in young transgenic mice (before significant changes in the lymphoid subpopulations) by in vitro assays. Assays were used to explore T-cell proliferation and activation induced by TCR engagement, survival to growth factor deprivations, resistance to apoptosis induced by CD3 re-stimulation and IL15-induced proliferation (indicative of self-renewal properties of CD8m cells). However, no significant difference was found in T cells from transgenic mice as compared with their control siblings. These negative results contrasted with the abnormalities in cellular behavior of untransformed T cells from TCL1 transgenic mice.7 These differences are surprising, given that TCL1 and MTCP1 belong to the same oncogene family and share biochemical and biological properties, but may result from subtle differences between TCL1 and MTCP1 oncogenic functions, or from different expression levels and patterns of these transgenes.

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Acknowledgements

We thank M Chopin and I Grandjean for their animal expertise, Dr O Lantz and his lab members for helpful discussions, technical advice and flow cytometry expertise, Dr F Moreau-Gachelin and Dr D Williamson for careful reading. This work was supported by funds from the Institut National de la Santé et de la Recherche Médicale (INSERM), Cancéropôle Ile-de-France and Institut Curie, Section de Recherche. M Joiner and E Le Toriellec were supported by grants from the Ministère de la Recherche et de la Technologie (MRT), and Dr G Despouy was supported by the Fondation de France and the Association Pour la Recherche sur l’Ataxie-Télangiectasie (APRAT).

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  1. Institut Curie, Centre de Recherche, 26 rue d’Ulm, INSERM, U509, F-75248, Paris, France

    M Joiner, E Le Toriellec, G Despouy & M H Stern

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Correspondence to M H Stern.

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Joiner, M., Le Toriellec, E., Despouy, G. et al. The MTCP1 oncogene modifies T-cell homeostasis before leukemogenesis in transgenic mice. Leukemia 21, 362–366 (2007). https://doi.org/10.1038/sj.leu.2404476

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