Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course

Abstract

Sixty-four patients with adult T-cell leukemia/lymphoma (ATL; 18 patients with indolent subtype and 46 with aggressive subtype) associated with human T-lymphotropic virus type 1 (HTLV-1) were analyzed using comparative genomic hybridization (CGH). The most frequent observations were gains at chromosomes 14q, 7q, and 3p and losses at chromosomes 6q and 13q. Chromosome imbalances, losses, and gains were more frequently observed in aggressive ATL than in indolent ATL, with significant differences between the 2 ATL subtypes at gains of 1q and 4q. An increased number of chromosomal imbalances was associated with a significantly shorter survival in all patients. A high number of chromosomal losses was associated with a poor prognosis in indolent ATL, whereas the presence of 7q؉ was marginally associated with a good prognosis in aggressive ATL. Paired samples (ie, samples obtained at different sites from 4 patients) and sequential samples from 13 patients (from 6 during both chronic disease and acute crisis and from 7 during both acute onset and relapse) were examined by CGH and Southern blotting for HTLV-1. All but 2 paired samples showed differences on CGH assessment. Two chronic/crisis samples showed distinct results regarding both CGH and HTLV-1 integration sites, indicating clonal changes in ATL at crisis. In 11 patients, the finding of identical HTLV-1 sites and clonally related CGH results suggested a common origin of sequential samples. In contrast to chronic/ crisis samples, CGH results with all acute/ relapse sample pairs showed the presence of clonally related but not evolutional subclones at relapse, thereby suggesting marked chromosomal instability. In summary, clonal diversity is common during progression of ATL, and CGH alterations are associated with clinical course. (Blood. 2001;97:3875-3881)

Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-β1-mediated growth suppression in adult T-cell leukemia/lymphoma

“…ATLL occurs in 3-5% of HTLV-1 carriers following a long latency period, which can range from 40 to 60 years (Yasunaga and Matsuoka, 2003). ATLL cells are derived from the malignant clonal expansion of an HTLV-1-infected CD4 þ T lymphocyte that has accumulated genetic lesions, including the activation of oncogenes or inactivation of tumorsuppressor genes (Tsukasaki et al, 2001). A previous study from our laboratory discovered these genetic lesions by spectral karyotyping with a high-density single-nucleotide polymorphism array and comparative genomic hybridization in ATLL; we found that the T-cell transcription factor (TCF8)/zinc-finger E-box binding homeobox 1 (ZEB1) was a candidate tumor suppressor in ATLL (Hidaka et al, 2008).…”

Molecular cytogenetic detection of chromosomal breakpoints in T-cell receptor gene loci

“…Breakpoints in 14q11 and 14q32, as well as genomic amplifications of 14q32, are recurrent in ATLL. 44,45 However, not all cases with 14q11 breaks appear to involve TRCA/D. Moreover, the breaks in 14q32 in ATLL seem not to target TCL1.…”

Repression of IRF-4 target genes in human T cell leukemia virus-1 infection

“…The HTLV-1 viral Tax protein was shown to interact with human MAD1 (HsMAD1) protein and compromise its function by preventing homodimerization as well as heterodimerization with HsMAD2, thus leading to an inhibition of the M checkpoint (Campbell et al, 2001;Jin et al, 1998;Kasai et al, 2001;Neuveut and Jeang, 2002). ATL cells are karyotypically abnormal and are frequently present as pleiomorphic multinucleated giant cells (Itoyama et al, 2001;Kamada et al, 1992;Sadamori, 1991;Sadamori et al, 1991;Tsukasaki et al, 2001;Yoshida, 2001); the TaxHsMAD1 interaction and the IRF-4 mediated downregulation of cyclin B1 and EB1 thus provide a molecular explanation for the HTLV-I-induced karyotypic abnormalities in ATL cells (Figure 7).…”