TY - JOUR
T1 - BCR-ABL alternative splicing as a common mechanism for imatinib resistance
T2 - Evidence from molecular dynamics simulations
AU - Lee, Tai Sung
AU - Ma, Wanlong
AU - Zhang, Xi
AU - Giles, Francis
AU - Cortes, Jorge
AU - Kantarjian, Hagop
AU - Albitar, Maher
PY - 2008/12/1
Y1 - 2008/12/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-08-0482
DO - 10.1158/1535-7163.MCT-08-0482
M3 - Article
C2 - 19056677
AN - SCOPUS:57749110998
SN - 1535-7163
VL - 7
SP - 3834
EP - 3841
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 12
ER -