title: ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children.
abstract: We examined clinical, morphologic, and cytogenetic features and ALL-1 (MLL, Htrxl, HRX) gene rearrangements in 17 cases of secondary leukemia that occurred 11 months to 9 years from diagnoses of primary cancers in children who received topoisomerase II inhibitors or developed secondary leukemias typical of those associated with this therapy. Primary diagnoses included nine solid tumors and eight leukemias. Ten secondary leukemias were acute myeloid leukemia (AML), one was of mixed lineage, two were acute lymphoblastic leukemia (ALL), and four presented as myelodysplasia. Of 15 cases with 11q23 involvement, 11 (73%) were cytogenetically identifiable; four cases had molecular rearrangement only. By Southern blot, rearrangements within the ALL-1 gene were similar to sporadic cases. The results of this analysis suggest the following: (1) In most pediatric cases of topoisomerase II inhibitor-associated leukemia, there is disruption of the breakpoint cluster region of the ALL-1 gene at chromosomal band 11q23. (2) Exposure histories vary in secondary 11q23 leukemia, as the only topoisomerase II inhibitor was dactinomycin in one case, and, in another case, no topoisomerase II inhibitor was administered. (3) There is clinical, morphologic, cytogenetic, and molecular heterogeneity in pediatric secondary 11q23 leukemia. (4) There are some survivors of pediatric secondary 11q23 leukemia, but the outcome is most often fatal.
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Felix
authors.forename: M R
authors.initials: MR
authors.lastname: Hosler
authors.forename: N J
authors.initials: NJ
authors.lastname: Winick
authors.forename: M
authors.initials: M
authors.lastname: Masterson
authors.forename: A E
authors.initials: AE
authors.lastname: Wilson
authors.forename: B J
authors.initials: BJ
authors.lastname: Lange
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000235:genetics*; D003609:Dactinomycin / Q000009:adverse effects*; D005047:Etoposide / Q000009:adverse effects*; D005260:Female; D005796:Genes; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy; D007951:Leukemia, Myeloid / Q000139:chemically induced* / Q000235:genetics* / Q000401:mortality; D007953:Leukemia, Radiation-Induced / Q000209:etiology; D008297:Male; D009190:Myelodysplastic Syndromes / Q000139:chemically induced* / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D016609:Neoplasms, Second Primary / Q000139:chemically induced* / Q000235:genetics* / Q000401:mortality; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000139:chemically induced* / Q000235:genetics* / Q000401:mortality; D011519:Proto-Oncogenes; D011878:Radiotherapy / Q000009:adverse effects; D013713:Teniposide / Q000009:adverse effects*; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D014178:Translocation, Genetic; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009363:Neoplasm Proteins; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D003609:Dactinomycin; D005047:Etoposide; D013713:Teniposide; D011495:Histone-Lysine N-Methyltransferase