Human Molecular Genetics, 2000, Vol. 9, No. 11 1671-1679
© 2000 Oxford University Press
DNA structural properties of AF9 are similar to MLL and could act as recombination hot spots resulting in MLL/AF9 translocations and leukemogenesis
University of Chicago Department of Medicine, Section of Hematology Oncology, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637-1470, USA, 1University of Oklahoma, Department of Chemistry and Biochemistry, 620 Parrington Oval, Room 311, Norman, OK 73019, USA and 2Loyola University Chicago, Cardinal Bernardin Cancer Center, 2160 South First Avenue, Maywood, IL 60153, USA
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 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.
+ These authors contributed equally to this work
§ To whom correspondence should be addressed. Tel: +1 773 834 1539; Fax: +1 773 702 3163; Email: pstrisse@medicine.bsd.uchicago.edu
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