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 Blood, 15 February 2008, Vol. 111, No. 4, pp. 2181-2189.
Prepublished online as a Blood First Edition Paper on November 19, 2007; DOI 10.1182/blood-2007-06-095182.

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NEOPLASIA

IL-2– and IL-15–induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes

Michal Marzec1, Xiaobin Liu1, Monika Kasprzycka1, Agnieszka Witkiewicz2, Puthiyaveettil N. Raghunath1, Mouna El-Salem1, Erle Robertson3, Niels Odum4, and Mariusz A. Wasik1

1 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia; 2 Department of Pathology, Jefferson Medical College, Philadelphia, PA; 3 Department of Microbiology, University of Pennsylvania, Philadelphia; and 4 Institute of Molecular Biology, University of Copenhagen, Copenhagen, Denmark

We examined functional status, activation mechanisms, and biologic role of the mTORC1 signaling pathway in malignant CD4+ T cells derived from the cutaneous T-cell lymphoma (CTCL). Whereas the spontaneously growing CTCL-derived cell lines displayed persistent activation of the TORC1 as well as the PI3K/Akt and MEK/ERK pathways, the IL-2–dependent cell lines activated the pathways in response to IL-2 and IL-15 but not IL-21. Activation of mTORC1 and MEK/ERK was nutrient dependent. The mTORC1, PI3K/Akt, and MEK/ERK pathways could also be activated by IL-2 in the primary leukemic, mitogen-preactivated CTCL cells. mTORC1 activation was also detected in the CTCL tissues in the lymphoma stage–dependent manner with the highest percentage of positive cells present in the cases with a large cell transformation. Rapamycin inhibited mTORC1 signaling and suppressed CTCL cell proliferation but showed little effect on their apoptotic rate when used as a single agent. Activation of the mTORC1, PI3K/Akt, and MEK/ERK pathways was strictly dependent on the Jak3 and Jak1 kinases. Finally, mTORC1 activation was transduced preferentially through the PI3K/Akt pathway. These findings document the selective {gamma}c-signaling cytokine-mediated activation of the mTORC1 pathway in the CTCL cells and suggest that the pathway represents a therapeutic target in CTCL and, possibly, other T-cell lymphomas.


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