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Immunogenotype Changes Prevail in Relapses of Young Children with TEL-AML1-Positive Acute Lymphoblastic Leukemia and Derive Mainly from Clonal Selection

Authors' Affiliations: ¹ Children's Cancer Research Institute; ² St. Anna Kinderspital, Vienna, Austria; ³ M. Tettamanti Research Center, Pediatric Clinic, San Gerardo Hospital, University of Milan Bicocca, Monza, Italy; ⁴ Department of Immunology, Erasmus MC Rotterdam, Rotterdam, the Netherlands; ⁵ Department of Pediatrics, University of Padova, Padua, Italy; ⁶ Department of Pediatrics, Charite Medical Center, Berlin, Germany; ⁷ Department of Pediatrics, Hannover Medical School, Hannover, Germany; and ⁸ Department of Pediatrics, Justus Liebig University, Giessen, Germany

Requests for reprints: E. Renate Panzer-Grümayer, Children's Cancer Research Institute, Kinderspitalgasse 6, 1090 Vienna, Austria. Phone: 43-1-40170431; Fax: 43-1-4087230; E-mail: renate.panzer{at}ccri.at.

Purpose: Variations of the immunogenotype and TEL deletions in children with TEL-AML1+ acute lymphoblastic leukemia support the hypothesis that relapses derive from a persistent TEL-AML1+ preleukemic/leukemic clone rather than a resistant leukemia. We aimed at elucidating the relationship between the immunogenotype patterns at diagnosis and relapse as well as their clinical and biological relevance.

Patients and Methods: Immunoglobulin and T-cell receptor gene rearrangements were analyzed in 41 children with a TEL-AML1+ acute lymphoblastic leukemia and an early (up to 30 months after diagnosis; n = 12) or late (at 30 months or later; n = 29) disease recurrence by a standardized PCR approach.

Results: In 68% of the patients (group I), we identified differences in the immunogenotype patterns, whereas no changes were observed in the remaining 32% (group II). The divergence resulted more often from clonal selection than clonal evolution and consisted predominantly of losses (0-6, median 5) and/or gains (0-4, median 1) of rearrangements. The frequency and number of clonal immunoglobulin/T-cell receptor rearrangements in group I was higher at diagnosis (2-13, median 5) than at relapse (2-7, median 4), whereas it was the lowest in group II (1-5, median 3). Although group I children were younger at diagnosis, there was no correlation between particular immunogenotype patterns and remission duration.

Conclusion: These findings imply that the clonal heterogeneity in younger children most likely reflects an ongoing high recombinatorial activity in the preleukemic/leukemic cells, whereas the more uniform repertoire observed in older children mirrors end-stage rearrangement patterns of selected cell clones that evolved during the prolonged latency period.

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