Results from two new studies provide key mechanistic insights into the complex molecular events that cause a deadly type of leukemia. The research, published in the July issue of the journal Cancer Cell, published by Cell Press, illuminates specific mechanisms involved in development of acute promyelocytic leukemia (APL) and identifies promising new avenues to develop treatments for some of its variant forms.
APL is a cancer of the bone marrow that occurs when certain developing white blood cells get stuck at a highly proliferative and immature stage. The abnormal cells accumulate and eventually crowd out the normal, healthy blood cells. Most cases of APL are caused by the expression of the PML/RARA (promyelocytic leukemia/retinoic acid receptor alpha) oncogene. This oncogene is formed by an abnormal translocation between two chromosomes and gives rise to a protein called a fusion protein. In APL, the fusion protein, always involving the transcription factor RARA, acts as a potent transcriptional repressor that interferes with gene expression and prevents normal differentiation of white blood cells. Previous work of these two groups suggested that PML/RARA self-association, called homodimerization, and posttranslational modifications are important for transformation. In addition, retinoid X receptor (RXR) has been shown to be present in the DNA-bound PML/RARA oncogenic complex and is thought to play a role in the ability of the fusion protein to bind to DNA and regulate gene expression.
Dr. Chi Wai Eric So from The Institute of Cancer Research in London and Dr. Shuo Dong from Baylor College of Medicine in Houston and their colleagues characterized the transformation mechanisms involved in APL by functionally separating homodimerization and the intrinsic DNA-binding properties of RARA fusions from transformation of primary blood cells. The researchers found that homodimerization was not sufficient for RARA fusion-mediated transformation, but h
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Contact: Erin Doonan
edoonan@cell.com
617-397-2802
Cell Press
9-Jul-2007