New mutations detected by denaturing high performance liquid chromatography during screening of exon 6 bcr-abl mutations in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors

dc.creatorMascarenhas, CC
dc.creatorCunha, AF
dc.creatorMiranda, EC
dc.creatorZulli, R
dc.creatorSilveira, RA
dc.creatorCosta, FF
dc.creatorPagnano, KBB
dc.creatorDe Souza, CA
dc.date2009
dc.date2014-11-14T09:28:32Z
dc.date2015-11-26T17:14:14Z
dc.date2014-11-14T09:28:32Z
dc.date2015-11-26T17:14:14Z
dc.date.accessioned2018-03-29T00:02:35Z
dc.date.available2018-03-29T00:02:35Z
dc.identifierLeukemia & Lymphoma. Taylor & Francis Ltd, v. 50, n. 7, n. 1148, n. 1154, 2009.
dc.identifier1042-8194
dc.identifierWOS:000267371600015
dc.identifier10.1080/10428190902930496
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/75791
dc.identifierhttp://www.repositorio.unicamp.br/handle/REPOSIP/75791
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/75791
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1281767
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionPoint mutations within the ABL kinase domain are the most frequent mechanism for reactivation of kinase activity of the BCR-ABL gene and have been associated with clinical resistance to tyrosine kinase (TK) inhibitors in patients with CML, conferring a poor prognosis. T315I (Treonine-->Isoleucine) is a mutation in the exon 6 of BCR-ABL gene that makes the protein resistant to kinase inhibitors currently used for treating CML. Denaturing High-performance liquid chromatography (D-HPLC) allows for high throughput mutation screening. In this study, we screened mutations in exon 6 of the BCR-ABL gene in patients presenting failure or sub optimal response according to Leukemia Net criteria and correlated the presence of mutations with clinical outcome. Genomic DNA was extracted from peripheral blood samples from 93 patients with CML (5 intolerant and 88 resistant). The PCR product was analysed by D-HPLC, and the patients samples with abnormal D-HLPC profiles were submitted to automated sequencing, using specific primers. Overall survival (OS) was calculated from the date of mutation analysis, for the whole group and for both groups (mutation versus no mutation). We screened mutations in exon 6 of the BCR-ABL gene in 93 CML TKI - resistant patients. Twenty-three out of 93 samples (25%) showed an abnormal elution profile. Automated sequencing confirmed the presence of a nucleotide change in 19 out of 23 cases: one polymorphism, T315T, seven known point mutations: T315I, F317L, V339L, M351T, E355G and F359V and three novel mutations: C305R, D325D and I360S. OS for the whole group was 80% in a median observation time of 30 months. OS for patients without the mutation was 87% and with the mutation was 56%, in a median observation time of 37 and 10 months, respectively (p < 0.0001, RR = 68). D-HPLC is a practical and sensitive method for routine clinical monitoring for emergence of kinase domain mutations and may be useful for optimising therapy in CML. The screening of mutations in exon 6 is clinically relevant, once the presence of mutations confers a poor outcome. Early detection of emerging mutant clones may help in decision-making for alternative treatment.
dc.description50
dc.description7
dc.description1148
dc.description1154
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionFAPESP [06/54026-7]
dc.languageen
dc.publisherTaylor & Francis Ltd
dc.publisherAbingdon
dc.publisherInglaterra
dc.relationLeukemia & Lymphoma
dc.relationLeuk. Lymphoma
dc.rightsfechado
dc.rightshttp://journalauthors.tandf.co.uk/permissions/reusingOwnWork.asp
dc.sourceWeb of Science
dc.subjectD-HPLC
dc.subjectCML
dc.subjecttyrosine kinase inhibitors
dc.subjectBCR-ABL mutations
dc.subjectsurvival
dc.subjectSti-571 Cancer-therapy
dc.subjectPatients Resistant
dc.subjectDomain Mutations
dc.subjectClinical Resistance
dc.subjectCytogenetic Resistance
dc.subjectChronic Phase
dc.subjectBlast Crisis
dc.subjectImatinib
dc.subjectCml
dc.subjectGene
dc.titleNew mutations detected by denaturing high performance liquid chromatography during screening of exon 6 bcr-abl mutations in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors
dc.typeArtículos de revistas


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