Submitted June 13, 2007
Accepted October 21, 2007
IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes
Michal Marzec, Xiaobin Liu, Monika Kasprzycka, Agnieszka Witkiewicz, Puthiyaveettil N. Raghunath, Mouna El-Salem, Erle Robertson, Niels Odum, and Mariusz A. Wasik*
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Department of Pathology, Jefferson Medical College, Philadelphia, PA
Department of Microbiology, University of Pennsylvania, Philadelphia, PA
Institute of Molecular Biology, University of Copenhagen, Copenhagen, Denmark
* Corresponding author; email: wasik{at}mail.med.upenn.edu.
We examined functional status, activation mechanisms and biological role of 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, 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 impact 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 
c-signaling cytokine-mediated activation of the mTORC1 pathway in the CTCL cells and suggest that the pathway represents therapeutic target in CTCL and, possibly, other T-cell lymphomas.
