Structural Explanation For Some Cases Of Human Acute Myeloid Leukemia

Despite much progress over the past several decades, most adults who develop leukemia die of the disease or complications associated with therapy, and leukemia is still the most common cause of death in children with cancer.

Most, if not all, cases of human acute myeloid leukemia (AML) are caused by mutations in or rearrangements of genes. Among the most common gene rearrangements are those involving the transcription factor complex, core-binding factor (CBF). CBF consists of two parts, one that binds directly to DNA (CBFalpha) and a second one (CBFbeta) that helps CBFalpha bind DNA. All alpha-subunits share a region that is conserved throughout evolution known as the Runt domain. This domain is responsible for both binding to DNA and interacting with the beta-subunit. Three genes in mammals encode CBFalpha and mutations in these genes are associated with human diseases.

To understand how the disease-associated mutations affect DNA binding Allan Warren of the Medical Research Council in Cambridge, UK and coworkers determined the three dimensional X-ray crystal structure of a complex between the AML1 Runt domain, CBFbeta and DNA (Nature Structural Biology, Vol. 8, No. 4, 01 Apr 2001). An important finding that comes from the structure of the complex is that most of the disease-associated mutations are in places in the Runt domain that specifically recognize the DNA. Thus, the structure explains why human disease-associated mutations in leukemogenesis and cleidocranial dysplasia lead to a loss in DNA binding since mutations at these positions are unable to interact with the DNA as well.

Contact

Dr. Allan J. Warren
MRC Laboratory of Molecular Biology
Hills Road
Cambridge CB2 2QH
UK
Telephone: +44 1223 402 456
Fax: +44 1223 412 178
Email: ajw@mrc-lmb.cam.ac.uk

(C) Nature Structural Biology press release.

Message posted by: Trevor M. D'Souza