Mutations in the ABL kinase domain pre-exist the onset of imatinib treatment Export

@article{citeulike:4226116, abstract = {Imatinib (Gleevec) (formerly STI571) competitively targets the adenosine 5-triphosphate (ATP) binding site of the kinase domain of ABL and was recently approved for the treatment of chronic myeloid leukemia (CML). Point mutations occurring in the kinase domain of BCR-ABL have been identified as a cause of imatinib resistance. These mutations can be categorized into two groups: (1) mutations directly impairing the binding of imatinib but not ATP, and (2) mutations occurring in the ATP phosphate binding loop (P loop) or activation loop preventing the kinase to achieve conformation required for imatinib binding. Functional analysis of mutant BCR-ABL alleles in vitro has demonstrated four mutations (Q252H, F317L,M351T, E355G) to confer moderate resistance to imatinib, while T315I-, E255K-, Y253F-, and G250E-expressing cells are markedly resistant. Assay sensitivities and patient selection will affect the frequency of mutation detection. Another possible explanation for imatinib resistance is that mutated BCR-ABL-expressing cells might pre-exist the onset of treatment at levels below threshold detection (<20\%), then expand under selective pressure of imatinib treatment. Rare mutated cells were identified using a very sensitive allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) assay in pretreatment samples of five CML patients supporting the theory that point mutations pre-existed imatinib treatment. Imatinib-resistant patients may benefit from molecular genotyping so mutations can be identified and clinical therapy adjusted accordingly. Semin Hematol 40(suppl 2):80-82. {\copyright} 2003 Elsevier Inc. All rights reserved.}, author = {Rochelestienne, C. and Preudhomme, C.}, citeulike-article-id = {4226116}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/S0037-1963(03)70025-0}, citeulike-linkout-1 = {http://linkinghub.elsevier.com/retrieve/pii/S0037196303700250}, doi = {10.1016/S0037-1963(03)70025-0}, issn = {00371963}, journal = {Seminars in Hematology}, keywords = {bcrabl, gleevac, resistance}, month = {April}, number = {2}, pages = {80--82}, posted-at = {2009-03-26 21:58:39}, priority = {2}, title = {Mutations in the ABL kinase domain pre-exist the onset of imatinib treatment}, url = {http://dx.doi.org/10.1016/S0037-1963(03)70025-0}, volume = {40}, year = {2003} }

TY - JOUR ID - citeulike:4226116 L3 - citeulike-article-id:4226116 N2 - Imatinib (Gleevec) (formerly STI571) competitively targets the adenosine 5-triphosphate (ATP) binding site of the kinase domain of ABL and was recently approved for the treatment of chronic myeloid leukemia (CML). Point mutations occurring in the kinase domain of BCR-ABL have been identified as a cause of imatinib resistance. These mutations can be categorized into two groups: (1) mutations directly impairing the binding of imatinib but not ATP, and (2) mutations occurring in the ATP phosphate binding loop (P loop) or activation loop preventing the kinase to achieve conformation required for imatinib binding. Functional analysis of mutant BCR-ABL alleles in vitro has demonstrated four mutations (Q252H, F317L,M351T, E355G) to confer moderate resistance to imatinib, while T315I-, E255K-, Y253F-, and G250E-expressing cells are markedly resistant. Assay sensitivities and patient selection will affect the frequency of mutation detection. Another possible explanation for imatinib resistance is that mutated BCR-ABL-expressing cells might pre-exist the onset of treatment at levels below threshold detection (<20%), then expand under selective pressure of imatinib treatment. Rare mutated cells were identified using a very sensitive allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) assay in pretreatment samples of five CML patients supporting the theory that point mutations pre-existed imatinib treatment. Imatinib-resistant patients may benefit from molecular genotyping so mutations can be identified and clinical therapy adjusted accordingly. Semin Hematol 40(suppl 2):80-82. © 2003 Elsevier Inc. All rights reserved. IS - 2 JF - Seminars in Hematology SN - 00371963 EP - 82 TI - Mutations in the ABL kinase domain pre-exist the onset of imatinib treatment VL - 40 SP - 80 KW - bcrabl KW - gleevac KW - resistance AU - Rochelestienne, C AU - Preudhomme, C PY - 2003/04// UR - http://dx.doi.org/10.1016/S0037-1963(03)70025-0 ER -