title: Genomic characterization of MOZ/CBP and CBP/MOZ chimeras in acute myeloid leukemia suggests the involvement of a damage-repair mechanism in the origin of the t(8;16)(p11;p13).
abstract: The t(8;16)(p11;p13), which is strongly associated with acute myeloid leukemia (AML) displaying monocytic differentiation, erythrophagocytosis by the leukemic cells, and a poor response to chemotherapy, fuses the MOZ gene (8p11) with the CBP gene (16p13). Although genomic rearrangements of MOZ and CBP have been detected using fluorescence in situ hybridization and Southern blot analyses, characterization of the breakpoints at the sequence level has never been performed. We have sequenced the breakpoints in four t(8;16)-positive AML cases with the aim to identify molecular genetic mechanisms underlying the origin of this translocation. In addition, an exon/intron map of the MOZ gene was constructed, which was found to be composed of 17 exons. Long-range-PCR with CBP forward primers in exon 2 and MOZ reverse primers in exon 17 as well as with a MOZ forward primer in exon 16 and a CBP reverse primer in intron 2 successfully amplified CBP/MOZ and MOZ/CBP hybrid genomic DNA fragments in all four AMLs. The breaks clustered in both CBP intron 2 and MOZ intron 16, and were close to repetitive elements, and in one case an Alu-Alu junction for the CBP/MOZ hybrid was identified. Additional genomic events (i.e., deletions, duplications, and insertions) in the breakpoint regions in both the MOZ and CBP genes were found in all four cases. Thus, the t(8;16) does not originate through a simple end-to-end fusion. The findings of multiple breaks and rearrangements rather suggest the involvement of a damage-repair mechanism in the origin of this translocation.
authors.affiliation: Department of Clinical Genetics, University Hospital, Lund, Sweden. ioannis.panagopoulos@klingen.lu.se
authors.forename: Ioannis
authors.initials: I
authors.lastname: Panagopoulos
authors.forename: Margareth
authors.initials: M
authors.lastname: Isaksson
authors.forename: Charlotta
authors.initials: C
authors.lastname: Lindvall
authors.forename: Anna
authors.initials: A
authors.lastname: Hagemeijer
authors.forename: Felix
authors.initials: F
authors.lastname: Mitelman
authors.forename: Bertil
authors.initials: B
authors.lastname: Johansson
mesh_terms: D000123:Acetyltransferases / Q000235:genetics*; D000208:Acute Disease; D000328:Adult; D000368:Aged; D001483:Base Sequence / Q000235:genetics; D050882:CREB-Binding Protein; D019457:Chromosome Breakage / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D051548:Histone Acetyltransferases; D006801:Humans; D007438:Introns / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: C470261:CBP-MOZ fusion protein, human; C470260:MOZ-CBP fusion protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D000123:Acetyltransferases; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051548:Histone Acetyltransferases; C108712:KAT6A protein, human