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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.
Submitted June 13, 2007
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA * 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
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