Contributions
Type: Publication Only
Background
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the expression of the BCR-ABL oncoprotein, which is essential for the pathogenesis of the disease. Imatinib, an ATP-competitive selective inhibitor of BCR-ABL, has unprecedented efficacy for the treatment of CML. Nevertheless resistance to imatinib is observed in over 30% cases of CML. Several cellular and genetic mechanisms of imatinib resistance have been proposed, including overexpression of the BCR-ABL gene, the tyrosine kinase domain mutations, pharmacokinetic and pharmacodynamic factors.
Aims
The purpose of this study was to investigate the mechanisms of resistance to imatinib in CML patients.
Methods
We have analyzed mRNA level of BCR-ABL gene by quantitative real time RT-PCR in 114 patients and have studied BCR-ABL mutations in patients with high level of expression of fusion gene. Mutation status was studied by direct sequencing of BCR-ABL cDNA samples.
Results
BCR-ABL mutations were founded in 16 (32%) patients with resistance to imatinib treatment. The mutation spectrum included four missense mutation: M351T (7 cases), T315I (4), T315I+M351T (2), M244V (1) and H396R (1). Next we conducted a search for microRNAs specifically targeting 3’UTR of BCR-ABL, using the miRBASE program to scan human genome (http://microrna.sanger.ac.uk/) and analyzed microRNAs expression profile. The down-regulation of miR-203-b (25-fold), mir-323 (4-fold) and miR-196-b (2-fold) in the group of patients with resistance was discovered.
Summary
In conclusion, our data showed that mutations in the BCR-ABL kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors in CML patients, but resistance mechanisms might also be regulated by microRNAs.
Keyword(s): Chronic myeloid leukemia, Imatinib resistance, Mutation
Session topic: Publication Only
Type: Publication Only
Background
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the expression of the BCR-ABL oncoprotein, which is essential for the pathogenesis of the disease. Imatinib, an ATP-competitive selective inhibitor of BCR-ABL, has unprecedented efficacy for the treatment of CML. Nevertheless resistance to imatinib is observed in over 30% cases of CML. Several cellular and genetic mechanisms of imatinib resistance have been proposed, including overexpression of the BCR-ABL gene, the tyrosine kinase domain mutations, pharmacokinetic and pharmacodynamic factors.
Aims
The purpose of this study was to investigate the mechanisms of resistance to imatinib in CML patients.
Methods
We have analyzed mRNA level of BCR-ABL gene by quantitative real time RT-PCR in 114 patients and have studied BCR-ABL mutations in patients with high level of expression of fusion gene. Mutation status was studied by direct sequencing of BCR-ABL cDNA samples.
Results
BCR-ABL mutations were founded in 16 (32%) patients with resistance to imatinib treatment. The mutation spectrum included four missense mutation: M351T (7 cases), T315I (4), T315I+M351T (2), M244V (1) and H396R (1). Next we conducted a search for microRNAs specifically targeting 3’UTR of BCR-ABL, using the miRBASE program to scan human genome (http://microrna.sanger.ac.uk/) and analyzed microRNAs expression profile. The down-regulation of miR-203-b (25-fold), mir-323 (4-fold) and miR-196-b (2-fold) in the group of patients with resistance was discovered.
Summary
In conclusion, our data showed that mutations in the BCR-ABL kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors in CML patients, but resistance mechanisms might also be regulated by microRNAs.
Keyword(s): Chronic myeloid leukemia, Imatinib resistance, Mutation
Session topic: Publication Only