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 Blood, 15 October 2004, Vol. 104, No. 8, pp. 2452-2457.
Prepublished online as a Blood First Edition Paper on June 24, 2004; DOI 10.1182/blood-2003-12-4426.

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NEOPLASIA

Translocation t(12;21) is related to in vitro cellular drug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia

Britt-Marie Frost, Erik Forestier, Göran Gustafsson, Peter Nygren, Marit Hellebostad, Olafur G. Jonsson, Jukka Kanerva, Kjeld Schmiegelow, Rolf Larsson, and Gudmar Lönnerholm, for the Nordic Society for Paediatric Haematology and Oncology

From the Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden; the Department of Clinical Sciences, Section of Pediatrics, University of Umeå, Sweden; the Department of Pediatric Oncology, Karolinska Institute, Stockholm, Sweden; the Department of Oncology, Radiology and Clinical Immunology, University Hospital, Uppsala, Sweden; the Department of Pediatrics, Ullevål University Hospital, Oslo, Norway; the Department of Pediatrics, Landspitali University Hospital, Reykjavik, Iceland; Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland; Pediatric Clinic II, Rigshospitalet, Copenhagen, Denmark; and the Department of Medical Sciences, Section of Pharmacology, University Hospital, Uppsala, Sweden.

The t(12;21) (p13;q22) translocation resulting in ETV6/RUNX1 (previously named TEL/AML1) gene fusion is present in about 25% of children with precursor B-lineage acute lymphoblastic leukemia (B-ALL). We successfully tested 275 precursor B-ALL samples from children aged 1 to 17 years to determine the relation between t(12;21) and in vitro cellular drug resistance, measured by the fluorometric microculture cytotoxicity assay (FMCA). Samples from 83 patients (30%) were positive for t(12;21). The ETV6/RUNX1+ samples were significantly more sensitive than ETV6/RUNX1– samples to doxorubicin, etoposide, amsacrine, and dexamethasone, whereas the opposite was true for cytarabine. After matching for unevenly distributed patient characteristics, that is, excluding patients with high hyperdiploidy (> 51 chromosomes), t(9; 22), t(1;19), or 11q23 rearrangement, the ETV6/RUNX1+ samples remained significantly more sensitive to doxorubicin (P = .001) and etoposide (P = .001). For the other drugs tested (amsacrine, cytarabine, dexamethasone, prednisolone, vincristine, 6-thioguanine, and 4-hydroperoxy-cyclophosphamide), no significant difference in cellular drug sensitivity was found. In conclusion, we found that the presence of the t(12;21) translocation in childhood precursor B-ALL is associated with a high tumor cell sensitivity to doxorubicin and etoposide. High throughput techniques should now be used to elucidate the cellular mechanisms by which ETV6/RUNX1 gene fusion is linked to increased sensitivity to these drugs.


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Hepatocyte Growth Factor Receptor c-MET Is Associated with FAS and When Activated Enhances Drug-induced Apoptosis in Pediatric B Acute Lymphoblastic Leukemia with TEL-AML1 Translocation
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