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

我们研究了人类嗜t淋巴病毒i型前病毒基因组和细胞基因组的异常与成人T-ceII白血病/淋巴瘤（ATL）多步骤白血病发生的关系，研究对象是由慢性和阴燃型等低级别恶性肿瘤发展而来的ATL。在13例由低分级发展为明显急性型的病例中，HTLV-I整合位点连续分析发现3例有明显改变。其中2例的TCR β重排模式也发生了变化，表明出现了一个不同于原低级别克隆的急性ATL克隆。我们将这种现象称为克隆变化。在一个案例中，TCR β重排带与原始克隆相同，表明克隆进化。对p15/16异常的连续分析显示，在低级别状态下，没有病例出现p15/16异常的缺失，但在进展到急性型后，我们发现了3例缺失。其中两个HTLV-I整合位点与原始克隆相同，表明克隆进化是通过获得p15/16缺失。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，在ATL疾病进展中经常观察到克隆变化，这与常见恶性肿瘤（如新生白血病）的克隆进化型疾病进展有很大不同。这种克隆性变化在eb病毒相关的b淋巴细胞恶性肿瘤中已有报道。总之，在疾病进展过程中发生的克隆变化可能是病毒癌变的一种特殊现象。

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.