This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wiemels, J. L. Articles by Yeh, R.-F. Search for Related Content PubMed PubMed Citation Articles by Wiemels, J. L. Articles by Yeh, R.-F.

Chromosome 12p Deletions in TEL-AML1 Childhood Acute Lymphoblastic Leukemia Are Associated with Retrotransposon Elements and Occur Postnatally

¹ Laboratory for Molecular Epidemiology, Department of Epidemiology and Biostatistics and ² Department of Pediatrics, University of California San Francisco, San Francisco, California; ³ Roche Nimblegen Systems, Madison, Wisconsin; ⁴ Division of Environmental Health Sciences and ⁵ Division of Epidemiology, School of Public Health, University of California at Berkeley, Berkeley, California; and ⁶ Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island

Requests for reprints: Joseph Wiemels, University of California San Francisco, Box 0441, 1 Irving Street, AC-34, San Francisco, CA 941143-0441. Phone: 415-514-0577; Fax: 415-502-7411; E-mail: joe.wiemels{at}ucsf.edu.

Key Words: Childhood acute lymphoblastic leukemia • Etiology of chromosomal deletion • Retrotransposon • Guthrie card • Backtracking

TEL-AML1 (ETV6-RUNX1) is the most common translocation in the childhood leukemias, and is a prenatal mutation in most children. This translocation has been detected at a high rate among newborns (1%); therefore, the rate-limiting event for leukemia seems to be secondary mutations. One such frequent mutation in this subtype is partial deletion of chromosome 12p, trans from the translocation. Nine del(12p) breakpoints within six leukemia cases were sequenced to explore the etiology of this genetic event, and most involved cryptic sterile translocations. Twelve of 18 del(12p) parent sequences involved in these breakpoints were located in repeat regions (8 of these in long interspersed nuclear elements). This stands in contrast with TEL-AML1, in which only 21 of 110 previously assessed breakpoints (19%) occur in DNA repeats (P = 0.0001). An exploratory assessment of archived neonatal blood cards revealed significantly more long interspersed nuclear element CpG methylations in individuals at birth who were later diagnosed with TEL-AML1 leukemia, compared with individuals who did not contract leukemia (P = 0.01). Nontemplate nucleotides were also more frequent in del(12p) than in TEL-AML1 junctions (P = 0.004), suggesting formation by terminal deoxynucleotidyl transferase. Assessment of six archived neonatal blood cards indicated that no del(12p) rearrangements backtracked to birth, although two of these patients were previously positive for TEL-AML1 using the same assay with comparable sensitivity. These data are compatible with a two-stage natural history: TEL-AML1 occurs prenatally, and del(12p) occurs postnatally in more mature cells with a structure that suggests the involvement of retrotransposon instability. [Cancer Res 2008;68(23):9935–44]