Lack of Association between C1236T, G2677T/A and C3435T Variants of the ABCB1 Gene and Imatinib Response in Iranian Chronic Myeloid Leukemia Patients
Maedeh KhosraviZahra KhalajNegar NouriMalihe NajafluValiollah MehrzadMohammad Forat-YazdiFariborz MokarianMansour Salehi
1
Citation
0
Reference
20
Related Paper
Citation Trend
Abstract:
Imatinib introduction caused to improve the clinical outcomes of chronic myeloid leukemia (CML) patients. Despite the significant effects of Imatinib, pharmacogenetic variables induced treatment resistant is also observed.. Imatinib is known as a P-glycoprotein (P-gp) efflux pump substrate encoded by the ABCB1 gene. The ABCB1 C1236T, G2677T/A and C3435T variants are possibly correlated with interindividual variation in pharmacokinetic response to Imatinib therapy. The present study aimed to examine the effect of ABCB1 gene variants on the therapeutic response of Imatinib in CML patients. Sixty-nine Iranian CML patients treated with Imatinib or Nilotinib were selected and divided into two groups of sensitive and resistant to Imatinib. C1236T and G2677T/A variants were genotyped by high resolution melting (HRM) analysis, and C3435T variant was genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Then, the results were compared between the two groups of patients. Our results showed that there were no significant differences between C1236T, G2677T/A and C3435T variants of ABCB1 gene and clinical response to Imatinib in the Iranian CML patients. According to the results of this study, genotyping of ABCB1 C1236T, G2677T/A and C3435T variants couldn’t help to predict the outcomes of Imatinib treatment in CML patients. So, these variants are not useful to make decisions about treatment, but it is suggested to do further investigations.Imatinib Mesylate
Philadelphia chromosome
ABL
Cite
Citations (0)
Imatinib Mesylate
breakpoint cluster region
Cite
Citations (28)
Imatinib Mesylate
Cite
Citations (0)
Imatinib Mesylate
Cite
Citations (0)
Introduction: Pre-existing BCR-ABL kinase domain mutation leads to Imatinib resistance. Methods: Retrospective analysis of 50 patients of Imatinib resistance was done in GCRI, from January 2014 till May 2014. Allelle Specific Oligonucleotide–Polymerase Chain Reaction (ASO-PCR) was performed on Genomic DNA, of peripheral blood mononuclear cells (PBMCs). Results: 47 (94%) were in Chronic phase, 2 (4%) in accelerated phase, 1 (2%) in blastic crisis. Median duration of Imatinib was 48 months. 43/50 had one or more than 1 mutation, T315I mutation in 5 (10%) patients, M351T in 32% (16/50) and F311L in 8. Conclusion: We report low cytogenetic response (25%) and durability of response to 600 mg of Imatinib, even in M351T mutation.
Chronic myelogenous leukemia
Imatinib Mesylate
ABL
genomic DNA
Cite
Citations (0)
ObjectiveTo study p53 codon 72 polymorphism in relation to cytogenetic response to imatinib treatment in patients with chronic myeloid leukemia (CML).BackgroundP53 polymorphism involves the substitution of an arginine for a proline at codon position 72. Many studies have investigated a genetic link between this variation and response to treatment in cancer.Patients and methodsThis study was conducted on 54 CML patients presented to the Clinical Oncology Department, Menoufia University during the period from June 2013 to April 2015. They were classified according to their cytogenetic response to imatinib therapy into 40 CML patients, cytogenetic responders to imatinib and 14 CML patients who are cytogenetic nonresponders to imatinib. Patients were genotyped for p53 codon 72 polymorphism using PCR. Follow up of the patients should be done after 3, 6, 9, 12, and 18 months after diagnosis, and was done by complete blood count, conventional cytogenetic, and fluorescence in-situ hybridization.ResultsAge, sex, hematologic, and cytogenetic response to imatinib in CML patients did not differ significantly among p53 codon 72 genotypes (arg/arg, arg/pro, and pro/pro) (P = 0.44, P = 0.45, and P = 0.11, respectively). P53 codon 72 polymorphism did not significantly alter the risk to imatinib cytogenetic unresponsiveness (P = 0.9221).ConclusionIt could be concluded that p53 codon 72 polymorphism is not associated with imatinib unresponsiveness in CML.
Imatinib Mesylate
Cite
Citations (0)
Protein kinase domain
ABL
Cite
Citations (0)
Imatinib Mesylate
Cite
Citations (0)
<p class="s4"><strong>Introduction:</strong> BCR-ABL kinase domain mutations represent the most important disease-related factor in chronic myelogenous leukemia (CML) resistance. Highly resistant clones may pre-exist and emerge rapidly. Patients with CML can acquire more than one BCR-ABL1 mutation, which may result in increased oncogenicity. <strong>Materials and Methods:</strong> Retrospective analysis of 50 patients of imatinib resistance was done in GCRI, from January 2014 to May 2014. Response to imatinib was defined according to the European LeukemiaNet 2009 criteria. Allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) was performed on genomic DNA, extracted from peripheral blood mononuclear cells. Results: Average age was 40.75 years, 33 were males and 17 females. 47 (94%) were in chronic phase, 2 (4%) in accelerated phase, and 1 (2%) in blastic crisis. 29/50 were having low EUTOS score, whereas SOKAL score was low in 20, intermediate in 21 while only 9 had high SOKAL at presentation. Median duration of imatinib was 48 months. 43/50 had one or more than 1 mutation, T315I mutation in 5 (10%) patients, and M351T in 32% (16/50). <strong>Conclusion:</strong> The presence of M351T mutation in mutant clone leads to the development of T315I mutations development, and the detection of M351T mutation in the initial months of the therapy has a prognostic significance. ASO-PCR is more sensitive method of the detection of such mutations as compared to direct sequencing. We report low cytogenetic response (25%) and durability of response to 600 mg of imatinib, even in M351T mutation, after 400 mg of imatinib for median period of 4 years.</p>
Chronic myelogenous leukemia
Imatinib Mesylate
Mutation Testing
clone (Java method)
ABL
Cite
Citations (1)
Background: Human organic cation transporter1 (hOCT1,SLC22A1),an influx transporter,is responsible for the uptake of Imatinib into chronic myeloid leukemia (CML)cells. Variation in clinical response to Imatinib has been observed with two nonsynonymous SNPs in hOCT1 gene ,namely M420del and M408V in some populations.
Aims: The study aimed to study hoct1 gene polymorphism M420del & M408V in CML patients treated with imatinib & their effect on hematological and molecular response to imatinib .Also, the synergistic effect of M408V & M420del on hematological and molecular response to imatinib were studied. Additionally, correlation of these polymorphisms with hoct1 gene expression was studied.
Methodology: Newly diagnosed CML patients, in the age group 18-80 years, with diagnosis confirmed by qualitative PCR for BCR-ABL1 fusion gene , who were to be initiated on Imatinib therapy were included in the study. Detection of BCR-ABL1 fusion gene transcripts for confirmation of diagnosis of CML by Qualitative multiplex RT-PCR ., evaluation of hOCT1 gene expression by Real Time quantitative RT-PCR (qPCR) and detection of gene polymorphism in hOCT1 gene: SNPs M420del (rs35191146) and M408V (rs628031) was done by Allele Specific PCR (AS-PCR).
Results: It was observed that patients having normal homozygous genotype for M408V and mutant homozygous or heterozygous genotype for M420del had an increased tendency towards imatinib resistance as compared to patients who had normal homozygous genotype for both the polymorphisms. On the other hand, this effect was not seen in patients with mutant homozygous or heterozygous genotypes for both polymorphisms.
Conclusions: Mutant M420del allele may be linked to poor outcome of imatinib treatment in CML, however simultaneous presence of mutant M408V allele appears to circumvent this effect.
Imatinib Mesylate
breakpoint cluster region
Cite
Citations (0)