HTLV-I infection is epidemiologically associated with an aggressive and fatal T-cell leukemia/lymphoma designated as Adult T-cell leukemia/lymphoma (ATLL). The transition from HTLV-I immortalized to HTLV-I transformed T cells has been associated with constitutive activation of the Jak/STAT signaling pathways as well as with a reduction of level of the tyrosine phosphatase-1 (SHP-1) expression. In early stages of ATLL viral proteins Tax and Rex are involved in up-regulated expression if IL-2 and IL-2R and possibly autocrine proliferation of infected cells. Although it is uncertain that in late stages of ATLL these proteins are still expressed in sufficient levels to maintain activation of the IL-2/IL-2R pathway. ATLL tumor cells consistently express high levels of IL-2R alpha chain and display constitutive Jak/STAT activation. IL-2/IL-2R signaling pathway is critical for continuous proliferation of ATLL cells and tumor formation in a mouse model. Because STAT proteins are potent inducers of anti-apoptotic proteins;interfering with HTLV-l-mediated Jak/STAT activation could trigger an apoptotic signal in leukemic cells. We have previously demonstrated that the viral protein HTLV-I p12 interacts with IL-2R beta and gamma chains leading to increase in STAT5-dependent transcription and propose that p12 plays an essential role in pathogenesis of adult T-cell leukemia. In the first aim we will identify and mutate the regions of p12 involved in binding to IL-2R beta and gamma chains and study their implication in Jak/STAT activation and transformation of human primary T-cells in vitro. Because HTLV-II does not activate Jak/STAT pathway, p12 chimera between HTVL-I and II will be constructed for complementation assays. In the second aim we will study expression of suppressors of cytokine signaling SOCS, CIS, and SHP-1 in p12+ and p12- HTLV-I immortalized cells and HTLV-I infected patient samples. We will investigate molecular mechanisms underlying Jak/STAT activation and its role in survival and telomerase activity of tumor cells. In the third aim we will study the role of p12-mediated activation of the IL- 2/IL-2R and Jak/STAT pathways in telomerase activation and long term cell proliferation. We will also characterize how p12 promote anti apoptotic signals in tumor cells. Results from these studies will impact our understanding of pathogenesis associated with deregulated Jak/STAT pathway and may reveal new therapeutic targets for the treatment of human T-cell leukemias and lymphomas.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Cell Biology Study Section (TCB)
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Read-Connole, Elizabeth Lee
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University of Kansas
Schools of Medicine
Kansas City
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Yao, Yuan; Bellon, Marcia; Shelton, Shary N et al. (2012) Tumor suppressors p53, p63TA?, p63TAy, p73?, and p73? use distinct pathways to repress telomerase expression. J Biol Chem 287:20737-47
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El Hajj, Hiba; El-Sabban, Marwan; Hasegawa, Hideki et al. (2010) Therapy-induced selective loss of leukemia-initiating activity in murine adult T cell leukemia. J Exp Med 207:2785-92
Bellon, Marcia; Baydoun, Hicham H; Yao, Yuan et al. (2010) HTLV-I Tax-dependent and -independent events associated with immortalization of human primary T lymphocytes. Blood 115:2441-8
Taylor, J M; Brown, M; Nejmeddine, M et al. (2009) Novel role for interleukin-2 receptor-Jak signaling in retrovirus transmission. J Virol 83:11467-76
Bellon, Marcia; Lepelletier, Yves; Hermine, Olivier et al. (2009) Deregulation of microRNA involved in hematopoiesis and the immune response in HTLV-I adult T-cell leukemia. Blood 113:4914-7
Fukumoto, Risaku; Andresen, Vibeke; Bialuk, Izabela et al. (2009) In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein. Blood 113:3726-34
Bellon, Marcia; Nicot, Christophe (2008) Central role of PI3K in transcriptional activation of hTERT in HTLV-I-infected cells. Blood 112:2946-55
Taylor, John M; Nicot, Christophe (2008) HTLV-1 and apoptosis: role in cellular transformation and recent advances in therapeutic approaches. Apoptosis 13:733-47

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