title: Translocation t(12;21) is related to in vitro cellular drug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Department of Women's and Children's Health, University Children's Hospital, SE-751 85 Uppsala, Sweden. britt-marie.frost@kbh.uu.se
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Frost
authors.forename: Erik
authors.initials: E
authors.lastname: Forestier
authors.forename: Göran
authors.initials: G
authors.lastname: Gustafsson
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
authors.forename: Marit
authors.initials: M
authors.lastname: Hellebostad
authors.forename: Olafur G
authors.initials: OG
authors.lastname: Jonsson
authors.forename: Jukka
authors.initials: J
authors.lastname: Kanerva
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.forename: Gudmar
authors.initials: G
authors.lastname: Lönnerholm
mesh_terms: D000293:Adolescent; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004171:Diploidy; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D023061:Gene Order; D006801:Humans; D007223:Infant; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D005047:Etoposide; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D014157:Transcription Factors; D000097764:ETS Translocation Variant 6 Protein; C493728:RUNX1 protein, human