Integration Patterns of HTLV-I Provirus in Relation to the Clinical Course of ATL: Frequent Clonal Change at Crisis From Indolent Disease

Abstract

We examined human T-lymphotropic virus type I (HTLV-I) DNA integration in 68 patients with adult T-cell leukemia/lymphoma (ATL) by Southern blotting using EcoRI, which does not cut within the 9 kb of the genome and probes for pX and gag-pol region of HTLV-I. We detected defective proviral integration as a monoclonal band of various sizes with the pX but not with the gag-pol probe, or a monoclonal band of less than 9 kb with the pX probe, in 20 patients (29.4%). These were designated defective (D) type. With both probes, a single band greater than 9 kb was detected in 34 (50.0%), designated complete (C) type, and two or more bands greater than 9 kb, were designated multiple (M) type, in 14 (20.6%). Advanced age, a high LDH value, and hypercalcemia were more frequent in D type patients. The median survival time (MST) was 6.8, 24.4, and 33.3 months, for D, C, and M types, respectively (log rank P = .006). Among 52 sequentially examined patients, the HTLV-I integration patterns changed in 4 (7.5%). In three of these four, the rearrangements of the T-cell receptor (TCR)b gene concomitantly changed, suggesting the appearance of a new ATL clone. Another patient had the same rearrangement of the TCRb gene, indicating clonal evolution. The HTLV-I integration pattern changed at crisis from indolent to aggressive ATL in three patients. These findings suggested that the HTLV-I integration patterns have clinical implications in ATL pathophysiology. In contrast to the clonal evolution characteristic of the multistep carcinogenesis of most human malignancies, the frequent clonal change of ATL at crisis is a peculiar phenomenon, probably reflecting the emergence of multiple premalignant clones in viral leukemogenesis as suggested in Epstein-Barr virus associated lymphomagenesis in the immunocompromised host.

Semiquantitative analysis of residual disease in patients treated for adult T‐cell leukaemia/lymphoma (ATLL)

“…Fluctuation of the frequency of circulating clones was also observed in all other patients. Together, these results reinforce the idea that there are multiple premalignant clones in the tumoural tissue from patients with ATLL (Tsukasaki et al, 1997;Cavrois et al, 1996) and suggest that some clones harbour distinct sensitivities to treatment. Tax transactivates the promoter of the multidrug resistance gene (MDR-1, Chuang et al, 1997) which confers resistance to chemotherapy.…”

“…This drawback may be circumvented by the use of primers specific to the tumourous rearrangement(s) (Chan et al, 1996). However, this more sensitive and specific approach cannot detect clonal change during the course of the disease (Tsukasaki et al, 1997;Shimamoto et al, 1993). Specific detection and semiquantitation of circulating infected clones with an absolute detection threshold of 2/15 000 (Cavrois et al, 1995) can be obtained with low amount of DNA by the quadruplicate LMPCR amplification of HTLV-1 integration sites.…”

“…There are few reports of ATLL harbouring distinct clones (Tsukasaki et al, 1997;Shimamoto et al, 1993;Kondo et al, 1995;Shibata et al, 1995), but patient 3 is the first documented case of clonal change occurring during treatment. Fluctuation of the frequency of circulating clones was also observed in all other patients.…”

Genomic instability and rapid clinical course in adult T-cell lymphoma/leukemia patient

“…Adult T-cell leukemia is one of the most aggressive human neoplasias and one of the few examples in which the primary etiologic agent, the human retrovirus HTLV-1 has been established [9,10]. HTLV-1 integrates into random sites in host chromosomal DNA, inducing genomic instability by interfering with mitotic checkpoints and reduced DNA repair [11,12]. The transformation is initiated by Tax, a regulatory protein encoded by the HTLV-I pX region [13].…”

Oligoclonal proliferation of human T‐cell leukaemia virus type 1 bearing T cells in adult T‐cell leukaemia/lymphoma without deletion of the 3′ provirus integration sites

“…Since there is a high level of genetic instability at the HTLV-1 Integration Sites Deletion in ATLL ᭧ 1998 Blackwell Science Ltd, British Journal of Haematology 101: 500-506 provirus locus harboured by the tumourous clone during ATLL (Ohshima et al, 1991;Shimamoto et al, 1994;Tamiya et al, 1996;Tsukasaki et al, 1997), one can hypothesize that microdeletions of the 3 0 integration sites may be more frequent in ATLL than at the asymptomatic phase of the infection. This could contribute to the IPCR pattern of oligoclonal expansion which accompanies the malignant clone in ATLL tumourous samples.…”