title: Cellular drug resistance in childhood acute myeloid leukemia is related to chromosomal abnormalities.
abstract: Specific cytogenetic abnormalities predict prognosis in childhood acute myeloid leukemia (AML). However, it is unknown why they are predictive and whether this is related to drug resistance. We previously reported that Down syndrome (DS) AML was associated with favorable resistance profiles. Here, we successfully analyzed drug resistance and (cyto-) genetic abnormalities of 109 untreated childhood AML samples using the 4-day total cell-kill methyl-thiazolyl tetrazolium (MTT) assay. Patients were classified according to the genetic abnormalities in the leukemic cells: t(8;21), inv(16), t(15;17), t(9;11), other 11q23 translocations, abnormalities of chromosome 5/7, trisomy 8 alone, normal karyotype, single random, and multiple (defined as 2 or more) abnormalities. The DS AML samples were excluded from the subgroup analysis. Samples with chromosome 5/7 abnormalities were median 3.9-fold (P =.01) more resistant to cytarabine than other AML samples. The t(9;11) samples were more sensitive to cytarabine (median 2.9-fold, P =.002), etoposide (13.1-fold, P =.001), the anthracyclines (2.9- to 8.0-fold, P <.01), and 2-chlorodeoxyadenosine (10.0-fold, P =.002) than other AML samples. The trisomy 8 and t(15;17) groups were too small for meaningful analysis. All other genetic subgroups did not show specific resistance profiles. Overall, we found no differences in drug resistance in samples taken at diagnosis between patients remaining in continuous complete remission (CCR) versus the refractory/relapsed patients. Within several genetic subgroups, however, relapsed/refractory patients were more cytarabine resistant when compared with patients remaining in CCR, but numbers were small and the results were not significant. We conclude that some, but not all, cytogenetic subgroups in childhood AML display specific drug-resistance profiles.
authors.affiliation: Department of Pediatric Hematology/Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. cm.zwaan@vumc.nl
authors.forename: Christian M
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Karel
authors.initials: K
authors.lastname: Hählen
authors.forename: Dieuwke R
authors.initials: DR
authors.lastname: Huismans
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Jochen
authors.initials: J
authors.lastname: Harbott
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Slater
authors.forename: Ursala
authors.initials: U
authors.lastname: Creutzig
authors.forename: Anjo J P
authors.initials: AJ
authors.lastname: Veerman
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D007446:Chromosome Inversion; D002877:Chromosomes, Human / Q000648:ultrastructure; D017338:Cladribine / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D007223:Infant; D007951:Leukemia, Myeloid / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects; D012008:Recurrence; D012074:Remission Induction; D013778:Tetrazolium Salts; D013844:Thiazoles; D014178:Translocation, Genetic; D014314:Trisomy
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D003561:Cytarabine; D017338:Cladribine; D005047:Etoposide; C022616:thiazolyl blue