BCR-ABL alternative splicing as a common mechanism for imatinib resistance: Evidence from molecular dynamics simulations

Tai Sung Lee, Wanlong Ma, Xi Zhang, Francis Giles, Jorge Cortes, Hagop Kantarjian, Maher Albitar

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)3834-3841
Number of pages8
JournalMolecular cancer therapeutics
Volume7
Issue number12
DOIs
StatePublished - Dec 1 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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