HTLV-I Tax-dependent and -independent events associated with immortalization of human primary T lymphocytes

• Published in: Blood Vol. 115; no. 12; pp. 2441 - 2448
• Main Authors: Bellon, Marcia, Baydoun, Hicham H., Yao, Yuan, Nicot, Christophe
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 25.03.2010; Americain Society of Hematology; American Society of Hematology
• Series: Lymphoid Neoplasia
• Subjects: Adult; Biological and medical sciences; Cell Division - drug effects; Cell Division - physiology; Cell Line, Transformed; Cell Transformation, Viral - physiology; Cellular Senescence - physiology; Chromosome Aberrations; Gene Products, tax - genetics; Genomic Instability - physiology; Hematologic and hematopoietic diseases; Human T-lymphotropic virus 1 - genetics; Humans; Interleukin-2 - pharmacology; Lymphoid Neoplasia; Lymphoma, T-Cell - pathology; Lymphoma, T-Cell - virology; Medical sciences; T-Lymphocytes - pathology; T-Lymphocytes - virology; Telomere - physiology; Virus; Human; Deltaretrovirus; Hematology; T-Lymphocyte; Primary; Retroviridae; Cell immortalization; HTLV-I virus
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-08-241117

Human T-cell leukemia virus type I (HTLV-I)–associated malignancies are seen in a small percentage of infected persons. Although in vitro immortalization by HTLV-I virus is very efficient, we report that Tax has poor oncogenic activity in human primary T cells and that immortalization by Tax is rare. Sustained telomerase activity represents one of the oncogenic steps required for Tax-mediated immortalization. Tax expression was required for the growth of primary T cells, but was not sufficient to propel T cells into cell cycle in the absence of exogenous interleukin-2 (IL-2). Tax was sufficient to activate the phosphoinositide-3 kinase (PI3K)/Akt pathway as shown by down regulation of Src homology phosphatase-1 and increased phosphorylation of Akt. We also found disruption of putative tumor suppressors IL-16 and translocated promoter region (TPR) in Tax-immortalized and HTLV-I–transformed cell lines. Our results confirmed previous observations that Tax activates the anaphase-promoting complex. However, Tax did not affect the mitotic spindle checkpoint, which was also functional in HTLV-I–transformed cells. These data provide a better understanding of Tax functions in human T cells, and highlight the limitations of Tax, suggesting that other viral proteins are key to T-cell transformation and development of adult T-cell leukemia.