DNA structural properties of AF9 are similar to MLL and could act as recombination hot spots resulting in MLL/AF9 translocations and leukemogenesis

Hum Mol Genet. 2000 Jul 1;9(11):1671-9. doi: 10.1093/hmg/9.11.1671.


The human AF9 gene at 9p22 is one of the most common fusion partner genes with the MLL gene at 11q23, resulting in the t(9;11)(p22;q23). The MLL-AF9 fusion gene is associated with de novo acute myelo-genous leukemia (AML), rarely with acute lymphocytic leukemia (ALL) and with therapy related leukemia (t-AML). The AF9 gene is >100 kb and two patient breakpoint cluster regions (BCRs) have been identified; BCR1 is within intron 4, previously called site A, whereas BCR2 or site B spans introns 7 and 8. Patient breakpoint locations were determined previously by RT-PCR and by genomic DNA cloning. In this study, we defined the exon-intron boundaries and identified several different structural elements in AF9 including a co-localizing in vivo DNA topo II cleavage site and an in vitro DNase I hypersensitive (DNase 1 HS) site in intron 7 in BCR2. Reversibility experiments demonstrated a religation of the topo II cleavage sites. The location of the in vivo topo II cleavage site was confirmed in vitro using a topo II cleavage assay. In addition, two scaffold associated regions (SARs) are located centromeric to the topo II and DNase I HS cleavage sites and border both patient breakpoint regions: SAR1 is located in intron 4, whereas SAR2 encompasses parts of exons 5-7. This study demonstrates that the patient breakpoint regions of AF9 share the same structural elements as the MLL BCR. We describe a DNA breakage and repair model for non-homologous recombination between MLL and its partner genes, particularly AF9.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Cell Line
  • Chromatin / genetics
  • DNA Topoisomerases, Type II / metabolism
  • DNA, Neoplasm / chemistry
  • DNA, Neoplasm / genetics*
  • DNA-Binding Proteins / genetics*
  • Deoxyribonuclease I / metabolism
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Introns
  • Jurkat Cells
  • K562 Cells
  • Leukemia / genetics*
  • Molecular Sequence Data
  • Myeloid-Lymphoid Leukemia Protein
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oncogene Proteins, Fusion / genetics*
  • Proto-Oncogenes*
  • Recombination, Genetic
  • Sequence Analysis, DNA
  • Transcription Factors*
  • Translocation, Genetic
  • Tumor Cells, Cultured


  • Chromatin
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • KMT2A protein, human
  • MLLT3 protein, human
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Transcription Factors
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Deoxyribonuclease I
  • DNA Topoisomerases, Type II

Associated data

  • GENBANK/AC000007
  • GENBANK/AC002050
  • GENBANK/AC002052
  • GENBANK/AC002053
  • GENBANK/AC002469