Gene copy number variation (CNV) and single nucleotide polymorphisms (SNPs) count as important sources for interindividual differences, including differential responsiveness to infection or predisposition to autoimmune disease as a result of unbalanced immunity. By developing an FCGR-specific multiplex ligationdependent probe amplification assay, we were able to study a notoriously complex and highly homologous region in the hu-

The TEL (ETV6)؊AML1 (CBFA2) gene fusion is the most common reciprocal chromosomal rearrangement in childhood cancer occurring in Ϸ25% of the most predominant subtype of leukemia-common acute lymphoblastic leukemia. The TEL-AML1 genomic sequence has been characterized in a pair of monozygotic twins diagnosed at ages 3 years, 6 months and 4 years, 10 months with common acute lymphoblastic leukemia. The twin leukemic DNA shared the same unique (or clonotypic) but nonconstitutive TEL-AML1 fusion sequence. The most plausible explanation for this finding is a single cell origin of the TEL-AML fusion in one fetus in utero, probably as a leukemia-initiating mutation, followed by intraplacental metastasis of clonal progeny to the other twin. Clonal identity is further supported by the finding that the leukemic cells in the two twins shared an identical rearranged IGH allele. These data have implications for the etiology and natural history of childhood leukemia.An extraordinary diversity of chromosomal molecular abnormalities has been identified in hematopoietic malignancies (1, 2). Among the most prominent are reciprocal chromosomal translocations that produce, via genetic recombination, inframe fusion genes and hybrid proteins (3, 4). Although details of the mechanisms involved remain to be elucidated, many of these genes encode transcription factors; their novel products are thought to endow clonal advantage via the imposition of an altered pattern of gene regulation (3, 4). One of the most frequent gene fusions so far described is that between TEL (or ETV6) and AML1 (or CBFA2). This rearrangement, although cryptic at the level of chromosome karyotype, occurs in approximately 25% of the predominant subtype of pediatric cancer and leukemia-common acute lymphoblastic leukemia (cALL)-in children diagnosed between the ages of 2 and 10 years (5, 6). The translocation t(12;21)(p13;q22) in ALL consistently involves the fusion of the protein dimerization encoding 5Ј region of the ETS-like gene TEL with almost the entire AML1 gene including its DNA binding region (with homology to Drosophila runt) and transactivation domain (reviewed in ref. 5). The chromosome 12 breakpoints cluster within a single intron of the TEL gene whereas AML1 breaks occur within the large and currently unsized first two introns of the AML1 gene on chromosome 21 (5-7). As with other fusion genes in leukemia, each patient's intronic breakpoints and subsequent fusion sequence are unique, providing a stable genomic marker of the derivative clone of cells. In the context of the etiology and natural history of childhood ALL, a key issue is when and how the TEL-AML1 fusion gene is generated and whether this is an early or initiating event. We report here a molecular analysis of the genomic fusion region of TEL-AML1 in the unusual situation of concordant leukemia in monozygotic twins. This analysis provides unequivocal evidence that this genetic lesion can be acquired during fetal hematopoiesis in utero.

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