In vitro, infected T-cells usually expand through an initial phase in which cells remain strictly dependent on exogenous IL-2, referred to as immortalized. After several months in culture a selected clonal or oligo-clonal cell population becomes independent of IL-2, referred to as transformed. Biochemically, the distinction between HTLV-1-immortalized and -transformed T-cells has been associated with constitutive activation of the Jak/STAT signaling pathways. These events may reproduce those that occur in vivo during the transition of patients from the asymptomatic/chronic to the acute type ATLL, with a median survival of 6-9 months. Constitutive activation of the Jak/STAT pathway and down regulation of the protein tyrosine phosphatase SHP-1 is a hallmark of the transformation process by HTLV-I. In addition, a positive correlation between proliferation of infected cells and Jak/STAT activation has been found in ATLL patients. Intriguingly, the Jak/STAT pathway is not activated in HTLV-II transformed cells in vitro or ex-vivo patient samples and HTLV-II does not induce human T-cell leukemia/ lymphoma. In early stages of ATLL viral proteins, Tax and Rex, are involved in up-regulated expression of IL-2 and the IL-2R (112) and possibly autocrine proliferation of infected cells. Although it is uncertain whether or not in late stages of ATLL these proteins are still expressed at sufficient levels to maintain activation of the IL-2/ IL-2R pathway, ATLL tumor cells always express high levels of IL-2Rα chain and usually display constitutive Jak/STAT pathway activation. In support of these observations previous studies have demonstrated that the IL-2/ IL-2R signaling pathway is critical for continuous proliferation of ATLL cells and tumor formation in a mouse model.
Nicot Laboratory
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