title: Distribution of 11q23 breakpoints within the MLL breakpoint cluster region in de novo acute leukemia and in treatment-related acute myeloid leukemia: correlation with scaffold attachment regions and topoisomerase II consensus binding sites.
abstract: A major unresolved question for 11q23 translocations involving MLL is the chromosomal mechanism(s) leading to these translocations. We have mapped breakpoints within the 8.3-kb BamHI breakpoint cluster region in 31 patients with acute lymphoblastic leukemia and acute myeloid leukemia (AML) de novo and in 8 t-AML patients. In 23 of 31 leukemia de novo patients, MLL breakpoints mapped to the centromeric half (4.57 kb) of the breakpoint cluster region, whereas those in eight de novo patients mapped to the telomeric half (3.87 kb). In contrast, only two t-AML breakpoints mapped in the centromeric half, whereas six mapped in the telomeric half. The difference in distribution of the leukemia de novo breakpoints is statistically significant (P = .02). A similar difference in distribution of breakpoints between de novo patients and t-AML patients has been reported by others. We identified a low- or weak-affinity scaffold attachment region (SAR) mapping just centromeric to the breakpoint cluster region, and a high-affinity SAR mapping within the telomeric half of the breakpoint cluster region. Using high stringency criteria to define in vitro vertebrate topoisomerase II (topo II) consensus sites, one topo II site mapped adjacent to the telomeric SAR, whereas six mapped within the SAR. Therefore, 74% of leukemia de novo and 25% of t-AML breakpoints map to the centromeric half of the breakpoint cluster region map between the two SARs; in contrast, 26% of the leukemia de novo and 75% of the t-AML patient breakpoints map to the telomeric half of the breakpoint cluster region that contains both the telomeric SAR and the topo II sites. Thus, the chromatin structure of the MLL breakpoint cluster region may be important in determining the distribution of the breakpoints. The data suggest that the mechanism(s) leading to translocations may differ in leukemia de novo and in t-AML.
authors.affiliation: Department of Medicine, University of Chicago, IL, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Broeker
authors.forename: H G
authors.initials: HG
authors.lastname: Super
authors.forename: M J
authors.initials: MJ
authors.lastname: Thirman
authors.forename: H
authors.initials: H
authors.lastname: Pomykala
authors.forename: Y
authors.initials: Y
authors.lastname: Yonebayashi
authors.forename: S
authors.initials: S
authors.lastname: Tanabe
authors.forename: N
authors.initials: N
authors.lastname: Zeleznik-Le
authors.forename: J D
authors.initials: JD
authors.lastname: Rowley
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use; D001483:Base Sequence; D001665:Binding Sites; D002503:Centromere / Q000648:ultrastructure; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000648:ultrastructure*; D002880:Chromosomes, Human, Pair 11 / Q000648:ultrastructure*; D016384:Consensus Sequence; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005047:Etoposide / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000235:genetics*; D011519:Proto-Oncogenes; D016615:Telomere / Q000648:ultrastructure; D013713:Teniposide / Q000009:adverse effects / Q000627:therapeutic use; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002843:Chromatin; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D005047:Etoposide; D013713:Teniposide; D011495:Histone-Lysine N-Methyltransferase; D004250:DNA Topoisomerases, Type II