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

分析成人 T 细胞白血病/淋巴瘤疾病进展过程中发现的前病毒和细胞基因组异常

• 批准号: 09671122
• 负责人: TOMONAGA Masao
• 金额: $ 1.79万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671122/
• 关键词: HTLV-I; ATL; clonal evolution; clonal change; p15; 16; RB; progression; multistep carcinogenesis; 成人T細胞白血病・リンパ腫; 多段階発癌; 癌抑制遺伝子

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.

本文对成人T细胞白血病/淋巴瘤（ATL）由慢性型、郁积型等低度恶性进展到急性型的13例患者，进行了人T淋巴细胞病毒Ⅰ型前病毒基因组和细胞基因组异常与多步白血病发生的关系的研究。对HTLV-1整合位点的连续分析揭示了三种情况下的明显变化。在其中两个中，TCR β重排的模式也发生了变化，表明与原始低级别克隆不同的克隆出现为急性ATL克隆。我们将这种现象称为克隆变化。1例TCR β重排区带与原始克隆区带一致，提示克隆性进化，对p15/16异常进行对比分析，发现在低度恶性时无一例缺失，但在进展为急性恶性时有3例缺失。在其中两个HTLV-I整合位点是相同的原始克隆，表明克隆进化收购的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疾病进展中观察到的克隆改变并不罕见，这与常见恶性肿瘤如原发性白血病中的克隆进化型疾病进展有很大不同。这种克隆性改变在EB病毒相关的B淋巴恶性肿瘤中已有报道。结论：在疾病进展过程中发生的克隆性改变可能是病毒致癌过程中的一种特殊现象。

项目成果

Yasuaki Yamada: "Deletions of p15 and/or p16 Genes as a Poor-Prognostic Factor in Adult T-cell Leukemia" Journal of Clinical Oncology. 15・5. 1778-1785 (1997)

Yasuaki Yamada：“p15 和/或 p16 基因的缺失是成人 T 细胞白血病的不良预后因素”，临床肿瘤学杂志 15・5（1997 年）。

Yasuaki Yamada: "Deletions of p15 and/or p16 genes as a Poor-Prognosis Factor in Adult T-cell Leukemia" Journal of Clinical Oncology. 15・5. 1778-1785 (1997)

Yasuaki Yamada：“p15 和/或 p16 基因的缺失是成人 T 细胞白血病的不良预后因素”，临床肿瘤学杂志 15・5（1997 年）。

Kunihiro Tsukasaki: "Integration Patterns of HTLV-I Provirus in Relation to the Clinical Course of ATL ; Frequent Clonal Change at Crisis from Indolent Disease" Blood. 89・3. 948-956 (1997)

Kunihiro Tsukasaki：“HTLV-I 原病毒与 ATL 临床病程相关的整合模式；惰性疾病危机时的频繁克隆变化”血液 89・3。

Kunihiro Tsukasaki: "Integration Patterns of HTLV-I Provirus in Relation to the Clinical Course of ATL ; Frequent Clonal Change at Crisis from Indolent Disease" Blood. 89-3. 948-956 (1997)

Kunihiro Tsukasaki：“HTLV-I 原病毒与 ATL 临床病程相关的整合模式；惰性疾病危机时频繁的克隆变化”血液。

Yasuaki Yamada: "Deletions of p15 and/ or p16 genes as a Poor-Prognosis Factor in Adult T-cell Leukemia" Journal of Clinical Oncology. 15・5. 1778-1785 (1997)

Yasuaki Yamada：“p15 和/或 p16 基因的缺失是成人 T 细胞白血病的不良预后因素”，临床肿瘤学杂志 15・5（1997 年）。