Tsukasaki K, Tsushima H, Yamamura M, Hata T, Murata K, Maeda T, Atogami S, Sohda H, Momita S, Ideda S, Katamine S, Yamada Y, Kamihira S, Tomonaga M
Department of Hematology, Nagasaki University School of Medicine, Japan.
Blood. 1997 Feb 1;89(3):948-56.
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.
我们通过使用EcoRI进行Southern印迹分析，检测了68例成人T细胞白血病/淋巴瘤（ATL）患者中I型人类嗜T淋巴细胞病毒（HTLV-I）的DNA整合情况。EcoRI不会切割HTLV-I基因组的9 kb区域内的片段，并使用针对HTLV-I的pX和gag-pol区域的探针。我们在20例患者（29.4%）中检测到缺陷型前病毒整合，表现为使用pX探针时出现各种大小的单一条带，而使用gag-pol探针时未出现，或者使用pX探针时出现小于9 kb的单一条带。这些被指定为缺陷（D）型。使用两种探针时，在34例患者（50.0%）中检测到大于9 kb的单一条带，被指定为完整（C）型，在14例患者（20.6%）中检测到两条或更多条大于9 kb的条带，被指定为多重（M）型。D型患者中高龄、高乳酸脱氢酶（LDH）值和高钙血症更为常见。D、C和M型的中位生存时间（MST）分别为6.8、24.4和33.3个月（对数秩检验P = 0.006）。在52例连续检查的患者中，4例（7.5%）的HTLV-I整合模式发生了变化。在这4例中的3例中，T细胞受体（TCR）β基因的重排也随之改变，提示出现了新的ATL克隆。另1例患者的TCRβ基因重排相同，表明发生了克隆进化。在3例患者中，HTLV-I整合模式在病情从惰性转变为侵袭性ATL的危急期发生了变化。这些发现提示HTLV-I整合模式在ATL病理生理学中具有临床意义。与大多数人类恶性肿瘤多步骤致癌的克隆进化特征不同，ATL在危急期频繁发生克隆变化是一种特殊现象，可能反映了病毒白血病发生过程中多个癌前克隆的出现，正如免疫功能低下宿主中Epstein-Barr病毒相关淋巴瘤发生所提示的那样。
