The uniform constitutive expression of IL-2 receptors (IL-2R) and the less frequent constitutive expression of IL-2 by human T-cell leukemia virus- (HTLV-) positive T-cell malignancies and the expression of both IL-2 and IL-2R by the gibbon ape leukemia virus- (GaLV-) infected MLA T-cell line pose several fascinating biological questions, including the precise role of the IL-2R in the proliferation of these malignancies. In this vein, an anti-sense mRNA will be made to the recently isolated IL-2R cDNA and expressed in HTLV-infected lymphoid cell lines to determine whether a direct blockade of IL-2R message will slow the proliferative rate of HTLV+ malignant cells. Recent studies suggest that the mechanism of IL-2R and IL-2 constitutive expression in these lines may involve a trans-acting factor that constitutively regulates the transcription of these genes. Two exprimental approaches will be applied to discern whether a trans mechanism is operative. First, hybrid IL-2 (or IL-2R) vectors will be made in which the bacterial chloramphenicol acetyltransferase gene is transcribed under the influence of putative IL-2 (or IL-2R) regulatory regions. Second, the complete gibbon and human IL-2 and IL-2R genes will be transfected cross-species and specific 3' cDNA probes will be used to distinguish the exogenous transcripts. One or both of these approaches should allow the determination of whether a transacting transcriptional factor is responsible for IL-2 and/or IL-2R gene expression in HTLV+ T-cell lines. If trans-acting factors are detected, the mechanism of constitutive IL-2/IL-2R expression will be further explored by determining whether the pX region of HTLV is the source of the factor(s), and by localizing sequences within the IL-2 and/or IL-2R genes that interact with trans-acting factors. If trans-acting factors are not detected, we will investigate possible cis mechanisms of cellular gene activation. These studies should provide further understanding of how the activation of cellular genes by HTLV and/or GaLV leads to T-cell malignancy, nd may suggest new therapies.
| Shaw, J P; Utz, P J; Durand, D B et al. (1988) Identification of a putative regulator of early T cell activation genes. Science 241:202-5 |
| Durand, D B; Shaw, J P; Bush, M R et al. (1988) Characterization of antigen receptor response elements within the interleukin-2 enhancer. Mol Cell Biol 8:1715-24 |
| Holbrook, N J; Gulino, A; Durand, D et al. (1987) Transcriptional activity of the gibbon ape leukemia virus in the interleukin 2 gene of MLA 144 cells. Virology 159:178-82 |
| Durand, D B; Bush, M R; Morgan, J G et al. (1987) A 275 basepair fragment at the 5' end of the interleukin 2 gene enhances expression from a heterologous promoter in response to signals from the T cell antigen receptor. J Exp Med 165:395-407 |
