Analysis of proviral and cellular genome abnormalities found during disease progression in adult T-cell leukemia/lymphoma

我们用成人T细胞II白血病/淋巴瘤(ATL)从慢性型和阴燃型等低度恶性进展到显性急性型的病例，对人类T淋巴细胞病毒I型前病毒前病毒基因组和细胞基因组的异常与成人T细胞II白血病/淋巴瘤(ATL)多步白血病发生的关系进行了研究。在其中两个克隆中，TCRβ重排模式也发生了改变，表明与原始低级别克隆不同的克隆出现了急性ATL克隆。我们将这种现象设计为克隆性变化。其中1例TCRβ重排条带与原始克隆相同，提示为克隆性进化。对p15/16异常的连续分析显示，在低度恶性状态下无一例出现缺失，但我们发现3例进展为急性型后缺失。其中两个克隆的HTLV-I整合位点与原始克隆相同，提示克隆进化是通过获得p15/16缺失来实现的。我们没有发现Rb异常与疾病进展同时发生的病例。有趣的是，我们经常观察到ATL疾病进展的克隆性变化，这与常见恶性疾病如新生白血病的克隆性进化型疾病进展有很大的不同。这种克隆性改变在Epstein-Barr病毒相关的B淋巴系恶性肿瘤中已有报道。综上所述，疾病进展过程中发生的克隆改变可能是病毒致癌过程中的一种特殊现象。

We have investigated on abnormaliteies of human T-lymphotropic virus type-I proviral genomes and cellular genomes in relation to multistep leukemogenesis of adult T-ceII leukemia/lymphoma (ATL) by using cases with ATL which progressed from low grade state of malignancies such as chronic type as well as smouldering type.1n 13 cases which progressed to overt acute type from the low grade types, consecutive analyses of HTLV-I integration sites disclosed apparent changes in three cases. In two of them, the pattern of TCR beta rearrangement changed also, indicating that a clone distinct from the original low grade clone appeared as acute ATL clone. We desiganted this phenomenon as clonal change. In one case TCR beta rearrangement band was identical to that of the original clone, indicating a clonal evolution.Consecutive analyses of p15/16 abnormalties revealed that no case showed deletion of them during low grade state, but we found three cases of deletion after progression to acute type. In two of them the HTLV-I integration site was identical to that of the original clone, suggesting clonal evolution by acquisition of the p15/16 deletion. We found no case with Rb abnormality occurring conincidentally with disease progression.It is interesting to have observed not infrequently the clonal changes in ATL disease progression, which are quite different from the clonal evolution-type disease progression in common maliganancies such as de novo leukemia.. Such a clonal cgange has been reported in Epstein-Barr virus-related B-lymphoid malignancies. In conclusion the clonal change occurring during disease progression may be a specific phenomenon in viral carcinogenesis.