Central role of PI3K in transcriptional activation of hTERT in HTLV-I–infected cells

Abstract

The persistence of human T-cell leukemia/ lymphoma virus-I (HTLV-I)-infected cells is dependent upon clonal expansion and upregulation of telomerase (hTERT). We have previously found that in interleukin (IL)-2-independent transformed HTLV-I cells, Tax strongly activates the hTERT promoter through nuclear factor-B (NF-B)-mediated Sp1 and c-Myc activation. In IL-2-dependent cells and adult T-cell leukemia/ lymphoma (ATLL) patient samples, however, Tax expression is very low toundetectable, yet these cells retain strong telomerase activity. This suggests the existence of compensatory mechanisms in IL-2-dependent cells and ATLL patients. In this study, we demonstrate that telomerase activity is significantly decreased upon IL-2 withdrawal in immortalized HTLV-I cell lines. Inhibition of PI3K or AKT signaling pathways reduced telomerase activity in HTLV-I cells. We found that IL-2/IL-2R signaling was associated with a PI3K-dependent/AKTindependent transcriptional up-regulation of the endogenous hTERT promoter. We found that activation of the PI3K pathway mediated cytoplasmic retention of the Wilms tumor (WTI) protein, which strongly suppressed the hTERT promoter. The importance of this regulatory pathway for telomerase expression is underscored by findings that the PI3K pathway is commonly found activated in cancer cells. IntroductionInterleukin-2 (IL-2) is required for the differentiation and longterm proliferation of T cells. IL-2 induces activation of Janus kinases and signal transducers and activators of transcription (JAK/STATs), leading to the induction of Shc/Ras/Raf/mitogenactivated protein kinase (MAPK) and PI3K/AKT pathways. 1 These cell signaling pathways promote cellular proliferation, survival, and differentiation 2 and are frequently deregulated in hematologic malignancies, including B-cell acute and chronic lymphoblastic leukemias, T-cell childhood and adult acute lymphoblastic leukemias, and various myeloid/lymphoid leukemias.Human T-cell leukemia/lymphoma virus-I (HTLV-I) is the causative agent of adult T-cell leukemia/lymphoma (ATLL). 3 In the early phases of infection, HTLV-I-infected cells are dependent upon the presence of IL-2, possibly contributing to the early clonal expansion of infected T cells through an IL-2/IL-2R autocrine/ paracrine loop. Disease progression, however, occurs in the absence of IL-2 secretion or expression, and when HTLV-Iinfected cells become transformed they no longer require IL-2. Although the steps leading to IL-2 independence remain to be elucidated, HTLV-I-transformed cells constitutively express the IL-2R and acquire constitutive activation of PI3K and JAK/STAT pathways required for the growth of HTLV-I-infected cells. [4][5][6][7] To sustain long-term proliferation, leukemic cells must acquire several oncogenic changes, 2 of which are bypassing apoptosis and replicative senescence. In ATLL cells, apoptosis is inhibited by increased expression of the antiapoptotic protein, Bcl-xL, 8 and alternate mechanisms. The avoidance of replicative senescence in ATLL cells is ...

JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells

“…IL-2 signaling has recently been shown to be associated with the upregulation of the hTERT promoter in Taxnegative HTLV-1-transformed cells (12). These findings suggest that telomerase is an attractive target for anticancer drug discovery in ATL; however, the mechanism of IL-2-dependent telomerase activation in Tax-negative ATL tumor cells has not been completely elucidated.…”

“…This mechanism is different from what was observed in NK cell tumors, in which mTOR and HSP90 are only implicated in the posttranslational regulation of hTERT (32). Recently, Bellon and colleagues reported that IL-2 signaling is associated with PI3K-dependent transcriptional upregulation of hTERT through the suppression of WT-1 in Taxnegative HTLV-1-transformed cells (12). This mechanism might also contribute to the IL-2-induced telomerase activity observed in this ATL system, even in the absence of Tax protein.…”

Epidemiología y bioinformática en el estudio de la Leucemia Linfoma de Células T del Adulto asociada a la infección con VLHT-1

“…La tendencia a la integración subtelomérica y telomérica registradas en el meta-análisis, pueden ser determinantes de la estabilidad cromosómica y la carcinogénesis (26). En el LLCTA se detiene el acortamiento crítico por la activación de la Telomerasa y de sus proteínas de enlace (TRF1, TRF2 y TIN2) (27).…”

Development of a novel redirected T-cell–based adoptive immunotherapy targeting human telomerase reverse transcriptase for adult T-cell leukemia

“…10 In HTLV-I-infected cells and ATL tumor cells, Tax or interleukin-2 (IL-2) signaling strongly activates the hTERT promoter through the nuclear factor-kB or PI3K pathway, [11][12][13] suggesting that expression of hTERT protein would be upregulated in ATL tumor cells. Clinical trials of anticancer immunotherapy targeting hTERT have already been conducted, and both the safety and induction of immune responses to hTERT have been reproducibly confirmed.…”