TEL deletion analysis supports a novel view of relapse in childhood acute lymphoblastic leukemia

被引:56
|
作者
Zuna, J
Ford, AM
Peham, M
Patel, N
Saha, V
Eckert, C
Köchling, J
Panzer-Grümayer, R
Trka, J
Greaves, M
机构
[1] Charles Univ Prague, Dept Paediat Haematol & Oncol, Sch Med 2, CLIP, Prague 15006 5, Czech Republic
[2] Inst Canc Res, Leukemia Res Fund Ctr Cell & Mol Biol, London, England
[3] Childrens Canc Res Inst, Vienna, Austria
[4] St Anna Childrens Hosp, Vienna, Austria
[5] Royal London Hosp, Canc Res UK, Childrens Canc Grp, London E1 1BB, England
[6] Humboldt Univ, Charite, Dept Paediat Oncol Haematol, Berlin, Germany
关键词
D O I
10.1158/1078-0432.CCR-04-0584
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.
引用
收藏
页码:5355 / 5360
页数:6
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