sirolimus and Sezary-Syndrome

Cutaneous T-cell lymphomas (CTCL) are characterised by clonal expansion of helper T lymphocytes that infiltrate the skin. Only a small number of cell lines exist to study cellular pathways leading to T-cell transformation and to identify new targets for intervention. We wanted to investigate the inhibition of mTOR as a possible therapeutic target in CTCL. Primary cells of patients with Sézary syndrome (SS) and conventional CTCL cell lines were analysed. Constitutive activation of mTOR was found, and concomitantly, we could show that rapamycin, a specific inhibitor of mTOR, inhibits CTCL cell growth in vitro by induction of cell cycle arrest. Using a previously established animal model for CTCL, we additionally observed upon rapamycin treatment tumor growth inhibition in vivo. In summary, primary cells from patients with SS as well as CTCL cell lines allowed us to identify mTOR as an important target for intervention.

Topics: Animals; Antibiotics, Antineoplastic; CD4-Positive T-Lymphocytes; Cell Culture Techniques; Cell Line, Tumor; Drug Evaluation, Preclinical; Humans; Mice; Mice, Nude; Sezary Syndrome; Signal Transduction; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

Signaling through the interleukin 2 receptor (IL-2R) involves phosphorylation of several proteins including Jak3, STAT5, and, in preactivated cells, STAT3. In the present study, we examined the functional status of the IL-2R-associated Jak/STAT pathway in malignant T lymphocytes from advanced skin-based lymphomas: anaplastic large T-cell lymphoma (ALCL) and Sezary syndrome (SzS). Proliferation of three ALCL cell lines (PB-1, 2A, and 2B) was partially inhibited by rapamycin, a blocker of some of the signals mediated by IL-2R, but not by cyclosporin A, FK-506, and prednisone, which suppress signals mediated by the T-cell receptor. All the cell lines expressed on their surface the high-affinity IL-2R (alpha, beta, and gamma c chains). They showed basal, constitutive phosphorylation, and coassociation of Jak3, STAT5, and STAT3. Weak basal phosphorylation of IL-2R gamma c was also detected. In regard to SzS, peripheral blood mononuclear cells from 10 of 14 patients showed basal phosphorylation of Jak3, accompanied by phosphorylation of STAT5 in 9 patients, and STAT3 in 4 patients. However, in vitro overnight culture of SzS cells without exogenous cytokines resulted in markedly decreased Jak3 and STAT5 phosphorylation, which could be reversed by stimulation with IL-2. This indicates that the basal phosphorylation of Jak3 and STAT5 in freshly isolated SzS cells is induced rather than constitutive. The basal activation of the Jak/STAT pathway involved in IL-2R signal transduction in ALCL and SzS cells reported here suggests that this pathway may play a role in the pathogenesis of cutaneous T-cell lymphomas, although the mechanism (induced versus constitutive) may vary between different lymphoma types.

Topics: Cell Membrane; Cyclosporine; DNA-Binding Proteins; Humans; Immunosuppressive Agents; Janus Kinase 3; Lymphocyte Activation; Lymphoma, T-Cell, Cutaneous; Milk Proteins; Phosphorylation; Polyenes; Prednisone; Protein Binding; Protein-Tyrosine Kinases; Receptors, Interleukin-2; Sezary Syndrome; Signal Transduction; Sirolimus; STAT3 Transcription Factor; STAT5 Transcription Factor; Tacrolimus; Trans-Activators; Tumor Cells, Cultured