Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials
Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials
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DOI：
10.1182/blood.v90.2.571.571_571_577
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发表时间：
1997-07-15
期刊：
影响因子：
20.3
通讯作者：
Biondi, A
中科院分区：
文献类型：
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作者：
Borkhardt, A;Cazzaniga, G;Biondi, A
分析白血病相关染色体易位的分子方法导致了预后相关亚组的鉴定。在儿童急性淋巴细胞白血病（ALL）中，最常见的易位t（9;22）和t（4;11）与较差的临床结局相关。最近发现位于染色体12 p13的TEL基因和位于染色体21 q22的AML 1基因参与了t（12;21）（p13;q22）易位。然而，通过常规细胞遗传学，这种染色体异常几乎检测不到，发生在不到0.05%的儿童ALL中。为了研究t（12;21）的分子等效物TEL/AML 1基因融合的频率，我们在德国柏林-法兰克福-明斯特（BFM）和意大利儿科肿瘤协会（AIEOP）多中心ALL治疗试验中进行了前瞻性筛选。我们分析了334例急性淋巴细胞白血病患儿连续转介5个月和9个月，分别。儿童ALL中t（12;21）的总体发生率为18.9%。TEL/AML 1嵌合产物阳性的63例患者年龄在1至12岁之间，除1例外，所有患者均显示CD 10和前B免疫表型。有趣的是，一个病例显示了前-前-B免疫表型。在B系亚群中，t（12;21）发生在22.0%的病例中。67例中有15例（24.6%）在超过20%的门控原始细胞中共表达至少两种髓系抗原（CD 13、CD 33或CDw 65）。63例TEL/AML 1阳性病例中有59例可获得DNA指数;仅4例患者检测到超二倍体DNA含量（大于或等于1.16），其余55例为非超二倍体。基于这一前瞻性分析，我们通过识别入组封闭的德国ALL-BFM-90和意大利ALL-AIEOP-91方案的B系ALL儿童亚组，回顾性评估了TEL/AML 1对预后的影响，这些儿童有足够的材料进行分析。对342例儿童进行了TEL/AML 1融合基因检测，阳性99例（28.9%）。表达TEL/AML 1融合mRNA的患者似乎比缺乏这种嵌合产物的患者具有更好的无事件生存（EFS）。TEL/AML 1基因重排阳性者3例（3.0%）复发，27例（11.1%）未重排者复发。迄今为止，B系ALL中唯一具有良好预后的亚组是超二倍体组（DNA指数大于或等于1.16
The molecular approach for the analysis of leukemia associated chromosomal translocations has led to the identification of prognostic relevant subgroups. In pediatric acute lymphoblastic leukemia (ALL), the most common translocations, t(9;22) and t(4;11), have been associated with a poorer clinical outcome. Recently the TEL gene at chromosome 12p13 and the AML1 gene at chromosome 21q22 were found to be involved in the translocation t(12;21)(p13;q22). By conventional cytogenetics, however, this chromosomal abnormality is barely detectable and occurs in less than 0.05% of childhood ALL. To investigate the frequency of the molecular equivalent of the t(12;21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankfurt-Munster (BFM) and Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) multicenter ALL therapy trials. We have analysed 334 unselected cases of pediatric ALL patients consecutively referred over a period of 5 and 9 months, respectively. The overall incidence of the t(12;21) in pediatric ALL is 18.9%. The 63 cases positive for the TEL/AML1 chimeric products ranged in age between 1 and 12 years, and all but one showed CD10 and pre-B immunophenotype. Interestingly, one case displayed a pre-pre-B immunophenotype. Among the B-lineage subgroup, the t(12;21) occurs in 22.0% of the cases. Fifteen of 67 (24.6%) cases coexpressed at least two myeloid antigens (CD13, CD33, or CDw65) in more than 20% of the gated blast cells. DNA index was available for 59 of the 63 TEL/AML1 positive cases; a hyperdiploid DNA content (greater than or equal to 1.16) was detected in only four patients, being nonhyperdiploid in the remaining 55. Based on this prospective analysis, we retrospectively evaluated the impact of TEL/AML1 in prognosis by identifying the subset of B-lineage ALL children enrolled in the closed German ALL-BFM-90 and Italian ALL-AIEOP-91 protocols who had sufficient material for analysis. A total of 342 children were investigated for the presence of TEL/AML1 fusion gene and 99 cases (28.9%) were positive. The patients expressing the TEL/AML1 fusion mRNA appeared to have a better event-free survival (EFS) than the patients who lacked this chimeric product. Whereas three of the TEL/AML1 positive cases (3.0%) have relapsed to date, 27 patients without TEL/AML1 rearrangement (11.1%) suffered from relapse. To date, the only subset of B-lineage ALL with a favorable prognosis has been the hyperdiploid group (DNA index greater than or equal to 1.16