Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells

Abstract

Interleukin-2 (IL-2

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

“…40 Both STAT3 and NFkB are known to be constitutively activated in CTCL. 26,27,41 Likewise, we observed expression of the active form of STAT5 (pY-STAT5) in malignant T cells in situ and in cell lysates from malignant T cell lines (Fig. S1A-D and E, respectively), confirming and extending other studies, 35 and suggesting that STAT5 is constitutively activated in CTCL.…”

“…In line with the results from STATs, resulting in malignant cell proliferation and survival. [23][24][25] In advanced disease, malignant T cells display a cytokine-independent, constitutive activation of JAK3, which drives a constitutive activation of STAT3 that, in turn, increases survival and resistance to apoptosis in malignant T cells, 26,27 and induces production of cytokines involved in eosinophilia and erythroderma (IL-5), as well as T helper 2 (Th2), 28 and Th17 29 cytokines. Furthermore, the pathway is believed to play a role in creating a pro-oncogenic inflammatory environment via production of VEGF 30 and IL-10 31 and induction of suppressor of cytokine signaling-3 (SOCS-3), 32 which confers resistance to IFNα in malignant T cells.…”

“…Malignant T cells lines (MyLa2059, PB2B, SeAx and SeZ4.1) and non-malignant T cell lines (MySi, MyLa1850) were obtained from CTCL patients and have been described perviously. 26,29,30,49 MAC2A is an anaplastic large T-cell lymphoma (ALCL) cell line established from a skin tumor in the progressive phase of the disease. 50 The Jurkat cell line (J-Tag) has been described elsewhere.…”

“…41 All cell lines were cultured as described previously. 26,29,30,[49][50][51] Peripheral blood mononuclear cells (PBMCs) from a healthy donor were isolated by density gradient centrifugation using Lymphoprep (Axis-Shield, PoC AS) as CTCL patients as well as PBMCs from healthy individuals also display a significant upregulation of BIC/miR-155 upon STAT5 activation by IL-2Rβγ cytokines (IL-2 and IL-15), indicating that transcriptional regulation of BIC by STAT5 is not a unique feature of malignant T cells, but a common regulatory pathway.…”

“…PBMCs from SS patients were labeled with antibodies for CD4 and CD26, as described before. 26 Subsequently, cells were sorted in a FACSAria cell sorter (BD) to obtain CD4+/CD26− as well as CD4+/ CD26+ populations.…”