BCR-ABL alternative splicing as a common mechanism for imatinib resistance: evidence from molecular dynamics simulations.
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.
Lee
Tai-Sung
TS
Consortium for Bioinformatics and Computational Biology and Department of Chemistry, University of Minnesota, 207 Pleasant Street Southeast, Minneapolis, MN 55455, USA. leex2750@umn.edu
Ma
Wanlong
W
Zhang
Xi
X
Giles
Francis
F
Cortes
Jorge
J
Kantarjian
Hagop
H
Albitar
Maher
M
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D001549:Benzamides; D003198:Computer Simulation; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl