Pharmacy News Article

2009 JAN 8 - (NewsRx.com) Research findings, 'BCR-ABL alternative splicing as a common mechanism for imatinib resistance: evidence from molecular dynamics simulations,' are discussed in a new report (see also Life Sciences). According to recent research from the United States, "Rare cases of chronic myelogenous leukemia (CML) express high levels of alternatively spliced BCR-ABL mRNA with a 35-bp insertion (35INS) between ABL kinase domain exons 8 and 9. This insertion results in a frameshift leading to the addition of 10 residues and truncation of 653 residues due to early termination."

"Sensitive PCR-based testing showed that 32 of 52 (62%) imatinib-resistant CML patients in chronic phase and 8 of 38 (21%) in accelerated or blast crisis expressed varying levels of the alternatively spliced BCR-ABL mRNA. A three-dimensional structural model of the 35INS ABL kinase domain complexed with imatinib was built using homology modeling, followed by molecular dynamics simulations," wrote T.S. Lee and colleagues, University of Minnesota.

The researchers concluded: "Simulation results showed that the new residues cause a significant global conformational change, altering imatinib binding in a way similar to that of the T315I mutation and, therefore, providing resistance to imatinib that depends on the level of expression."

Lee and colleagues published their study in Molecular Cancer Therapeutics (BCR-ABL alternative splicing as a common mechanism for imatinib resistance: evidence from molecular dynamics simulations. Molecular Cancer Therapeutics, 2008;7(12):3834-41).

For additional information, contact T.S. Lee, University of Minnesota, Consortium for Bioinformatics and Computational Biology and Dept. of Chemistry, 207 Pleasant Street Southeast, Minneapolis, MN 55455 USA..

Publisher contact information for the journal Molecular Cancer Therapeutics is: American Association Cancer Research, 615 Chestnut St., 17TH Floor, Philadelphia, PA 19106-4404, USA.