Genetic and epigenetic inactivation of tax gene in adult T‐cell leukemia cells

Abstract

To clarify the status of tax gene, we analyzed human T-cell leukemia virus type-I (HTLV-I) associated cell lines and fresh adult T-cell leukemia (ATL) cells. We compared 2 types of HTLV-I associated cell lines: one was derived from leukemic cells (leukemic cell line) and the other from nonleukemic cells (nonleukemic cell line). Although all nonleukemic cell lines expressed Tax, it could not be detected in 3 of 5 leukemic cell lines, in which nonsense mutation or deletion (60 bp) of tax genes, and DNA methylation in 5-LTR were identified as the responsible changes. We found such genetic changes of the tax gene in 5 of 47 fresh ATL cases (11%). The tax gene transcripts could be detected in 14 of 41 fresh ATL cases (34%) by RT-PCR. In ATL cases with genetic changes that could not produce Tax protein, the tax gene was frequently transcribed, suggesting that such cells do not need the transcriptional silencing. Although DNA methylation of 5-LTR was detected in the fresh ATL cases (19 of 28 cases; 68%), the complete methylation associated with transcriptional silencing was observed only in 4 cases. Since partial methylation could not silence the transcription, and the tax gene transcription was not detected in 27 of 41 cases (66%), the epigenetic change(s) other than DNA methylation is considered to play an important role in the silencing.

Viral epigenomes in human tumorigenesis

“…Furthermore, the 3 0 -LTR, from which HBZ is transcribed, has been found intact and unmethylated in all stages of ATL development in all previous studies (Koiwa et al, 2002;Takeda et al, 2004;Taniguchi et al, 2005), which is further evidence of this gene's importance in ATL maintenance. In addition to its role in ATL proliferation, HBZ has been associated with downregulation of viral transcription mediated by Tax through the 5 0 -LTR (McLaughlin-Drubin and Munger, 2008).…”

“…In this regard, it seems that Tax is necessary for initiating transformation, whereasHBZ maintains it (Matsuoka and Jeang, 2007). As in the case of the viruses already described in this review, this repression of a viral protein (Tax) could be associated with the evasion of the immune response, as Tax is the main target of the host's cytotoxic T-lymphocyte response (Takeda et al, 2004).…”

“…Besides deletions of 5 0 -LTR or mutations in the Tax gene, 5 0 -LTR DNA methylation of the provirus occurs in 15% of cases (Koiwa et al, 2002;Takeda et al, 2004;Taniguchi et al, 2005;Matsuoka and Jeang, 2007). Tax can also modulate its own expression by recruiting a histone methyltransferase (SUV39h1) to the 5 0 -LTR and inducing repressive histone modification on the chromatin through H3 K9 methylation (Kamoi et al, 2006).…”

“…Several studies have found DNA hypermethylation of the 5 0 -LTR in latency stages of ATL development that was associated with a lack of viral gene expression (Koiwa et al, 2002;Takeda et al, 2004;Taniguchi et al, 2005). Taniguchi and co-workers have demonstrated this in a more comprehensive study and have additionally shown that methylation occurs in internal provirus sequences .…”

PTHrP Gene Expression in Cancer: Do All Paths Lead to Ets?

“…Recent surveys of HTLV-1 Tax mRNA expression from human-patient samples suggest that exceedingly low levels of this nuclear factor are present in ATLL cells. 43,44 A model of ATLL-induced hypercalcemia using SCID/beige mice has recently been developed, and leukemia cells purified from hypercalcemic animals contain undetectable levels of Tax mRNA or protein. 45 Finally, a Q-RT-PCR-based survey of six HTLV-1 transformed cell lines demonstrated an inverse relationship between Tax and PTHrP expression.…”