Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome.

Abstract

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

Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway

“…We also tested three ALKÀTCL cell lines that share with the ALK þ TCL many characteristics including anaplastic cell morphology and CD30 antigen expression (Zhang et al, 1996). As controls we used the Epstein-Barr virus-transformed (EBV) þ and EBVÀ B-cell lines, all of which show persistent activation of the mTOR pathway, but only the former display simultaneous activation of the PI3K/ Akt pathway .…”

“…Our findings suggest that mTOR represents a potential novel therapeutic target in NPM/ALK-expressing ALK þ TCL and, in all likelihood, other ALKdriven malignancies. Our previous studies indicate that mTOR inhibitors hold promise as potential therapeutic agents in other types of lymphoma (Zhang et al, 1996;Wlodarski et al, 2005), with the effect on EBVtransformed B lymphocytes being the best documented (Majewski et al, 2000(Majewski et al, , 2003. Considering that mTOR inhibitors rapamycin and RAD001 are used as immunosuppressive drugs known to affect primarily T lymphocytes, ALK þ TCL cells may be quite sensitive to therapies targeting mTOR.…”

Transcriptional regulatory effects of lymphoma-associated NFKB2/lyt10 protooncogenes

“…The HUT78 cell line also contains alterations in c-myc (Finger et al, 1988), c-cbl (Blake andLangdon, 1992), and p53 (Tolomeo et al, 1998). Furthermore, alterations in JAK/STAT signaling have also been strongly implicated in the pathogenesis of human CTCL (Nielsen et al, 1997;Zhang et al, 1996). Loss of the IkB-like activity of p100 NF-kB-2 could lead to enhanced anti-apoptotic activity in these cells as a result of constitutive NF-kB activity (Beg and Baltimore, 1996;Liu et al, 1996;Sonenshein, 1997;Van Antwerp et al, 1996;Wang et al, 1996).…”

STAT signaling in the pathogenesis and treatment of leukemias

“…Constitutive STAT activation has been especially well characterized in leukemias, and a growing body of evidence in both acute and chronic leukemias suggests that derangements in the STAT signaling pathway may be critical to the development of cancer in hematopoietic cells (CatlettFalcone et al, 1999;Frank et al, 1997;GouilleuxGruart et al, 1996;Nieborowska-Skorska et al, 1999;Weber-Nordt et al, 1996;Zhang et al, 1996). The multitude of hematologic cancers which demonstrate abnormal STAT activation suggests that the STAT pathway may play an important role in the pathogenesis of malignancy and may serve as an attractive target of anti-cancer therapies.…”