Journal Article

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

Pamela L. Strissel, Reiner Strick, Ronald J. Tomek, Bruce A. Roe, Janet D. Rowley and Nancy J. Zeleznik-Le

in Human Molecular Genetics

Volume 9, issue 11, pages 1671-1679
Published in print July 2000 | ISSN: 0964-6906
Published online July 2000 | e-ISSN: 1460-2083 | DOI:
DNA structural properties of AF9 are similar to MLL  and could act as recombination hot spots resulting in MLL/AF9 translocations and leukemogenesis

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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 MLLAF9 fusion gene is associated with de novo acute myelo­genous 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.

Journal Article.  8409 words.  Illustrated.

Subjects: Genetics and Genomics

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