Zuna Jan, Ford Anthony M, Peham Martina, Patel Naina, Saha Vaskar, Eckert Cornelia, Köchling Joachim, Panzer-Grümayer Renate, Trka Jan, Greaves Mel
Leukemia Research Fund Centre for Cell and Molecular Biology, Institute of Cancer Research, London, United Kingdom.
Clin Cancer Res. 2004 Aug 15;10(16):5355-60. doi: 10.1158/1078-0432.CCR-04-0584.
TEL (ETV6)-AML1 (RUNX1) chimeric gene fusions are frequent genetic abnormalities in childhood acute lymphoblastic leukemia (ALL). They often arise prenatally as early events or initiating events and are complemented by secondary postnatal genetic events of which deletion of the non-rearranged, second TEL allele is the most common. This consistent sequence of molecular pathogenesis facilitates an analysis of the clonal origins of relapse in this leukemia, which has some unusual clinical features.
We compared the boundaries, by microsatellite mapping, of TEL deletions at relapse versus diagnosis in 15 informative patients. Moreover, we compared the relatedness of diagnostic and relapse clones using immunoglobulin and T-cell receptor genes rearrangements and clonotypic TEL-AML1 genomic fusion.
Five patients retained the apparent same size TEL deletion, seven had larger deletions, and three had smaller deletions at relapse. In all of the cases evaluated, the clonal relatedness of diagnostic and relapse cells was confirmed by the retention of clonotypic TEL-AML1 genomic sequence and/or at least one identical immunoreceptor gene rearrangement.
These data provide further evidence that TEL deletions are secondary to TEL-AML1 fusions in ALL. They are compatible with the novel idea that in at least some cases of childhood ALL, remission occurs with persistence of a preleukemic "fetal" clone, and subsequent relapse reflects the emergence of a new subclone from this reservoir after an independent "second hit," i.e., independent TEL deletion. To our knowledge, the study is the most extensive and comprehensive analysis of the relationship between diagnostic and relapse clones in childhood ALL presented thus far.
TEL（ETV6）-AML1（RUNX1）嵌合基因融合是儿童急性淋巴细胞白血病（ALL）中常见的基因异常。它们常常在产前作为早期事件或起始事件出现，并伴有出生后的继发性基因事件，其中未重排的第二个TEL等位基因的缺失最为常见。这种一致的分子发病机制序列有助于分析这种具有一些不寻常临床特征的白血病复发的克隆起源。
我们通过微卫星定位比较了15例信息充分的患者复发时与诊断时TEL缺失的边界。此外，我们使用免疫球蛋白和T细胞受体基因重排以及克隆型TEL-AML1基因组融合比较了诊断克隆和复发克隆的相关性。
5例患者复发时TEL缺失的大小与诊断时明显相同，7例患者的缺失更大，3例患者的缺失更小。在所有评估的病例中，通过克隆型TEL-AML1基因组序列的保留和/或至少一种相同的免疫受体基因重排，证实了诊断细胞和复发细胞的克隆相关性。
这些数据进一步证明了在ALL中TEL缺失继发于TEL-AML1融合。它们与以下新观点相符：在至少一些儿童ALL病例中，缓解是在白血病前期“胎儿”克隆持续存在的情况下发生的，随后的复发反映了在独立的“第二次打击”（即独立的TEL缺失）后，这个细胞库中出现了一个新的亚克隆。据我们所知，该研究是迄今为止对儿童ALL诊断克隆和复发克隆之间关系进行的最广泛、最全面的分析。
