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A single nucleotide polymorphism in cBIM is associated with a slower achievement of major molecular response in chronic myeloid leukaemia treated with imatinib.

Augis V, Airiau K, Josselin M, Turcq B, Mahon FX, Belloc F - PLoS ONE (2013)

Bottom Line: No mutation with amino-acid change was found in the BIM coding sequence.Similarly, this T allele was associated with the mutation frequency on the tyrosine kinase domain of BCR-ABL (p<0.001) and the presence of the T allele significantly lengthened the time to achieve a major molecular response (MMR).These results suggest that the analysis of the c465C>T SNP of BIM could be useful for predicting the outcome of imatinib-treated CML patients.

View Article: PubMed Central - PubMed

Affiliation: Université Bordeaux Segalen and INSERM U1035 Bordeaux, Bordeaux, France ; Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

ABSTRACT

Purpose: BIM is essential for the response to tyrosine-kinase inhibitors (TKI) in chronic myeloid leukaemia (CML) patients. Recently, a deletion polymorphism in intron 2 of the BIM gene was demonstrated to confer an intrinsic TKI resistance in Asian patients. The present study aimed at identifying mutations in the BIM sequence that could lead to imatinib resistance independently of BCR-ABL mutations.

Experimental design: BIM coding sequence analysis was performed in 72 imatinib-treated CML patients from a French population of our centre and in 29 healthy controls (reference population) as a case-control study. Real-time quantitative PCR (RT qPCR) was performed to assess Bim expression in our reference population.

Results: No mutation with amino-acid change was found in the BIM coding sequence. However, we observed a silent single nucleotide polymorphism (SNP) c465C>T (rs724710). A strong statistical link was found between the presence of the T allele and the high Sokal risk group (p = 0.0065). T allele frequency was higher in non responsive patients than in the reference population (p = 0.0049). Similarly, this T allele was associated with the mutation frequency on the tyrosine kinase domain of BCR-ABL (p<0.001) and the presence of the T allele significantly lengthened the time to achieve a major molecular response (MMR). Finally, the presence of the T allele was related to a decreased basal expression of the Bim mRNA in the circulating mononuclear cells of healthy controls.

Conclusion: These results suggest that the analysis of the c465C>T SNP of BIM could be useful for predicting the outcome of imatinib-treated CML patients.

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Related in: MedlinePlus

Relation between the C/C or T/T plus C/T BIM genotypes and the achievement of MMR.a: cDNAs from 64 patients followed in the laboratory for their Bcr-Abl expression were sequenced for the BIMEL coding region. The number of patients achieving a MMR before or after 18 months (left panel) or 24 months (right panel) was plotted as a function of the c465C>T genotype: C/C (white bars) or C/T plus T/T (grey bars). p indicates significance with the chi-square test. b: Kaplan-Meier analysis of the achievement of a MMR. The figure represents the probability to achieve a MMR (in %) as a function of the treatment duration (in months) for patients with the C/C genotype (continuous line) or patients with the C/T or T/T genotype (dotted line). c: cDNAs from 37 resistant patients were sequenced for both the BCR-ABL tyrosine kinase domain (TKD) and BIMEL coding region. The frequency of patients with non mutated or mutated TKD was plotted as a function of the c465C>T genotype. The numbers above the bars indicate the sample size. The p value was calculated using the Chi-square test.
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pone-0078582-g002: Relation between the C/C or T/T plus C/T BIM genotypes and the achievement of MMR.a: cDNAs from 64 patients followed in the laboratory for their Bcr-Abl expression were sequenced for the BIMEL coding region. The number of patients achieving a MMR before or after 18 months (left panel) or 24 months (right panel) was plotted as a function of the c465C>T genotype: C/C (white bars) or C/T plus T/T (grey bars). p indicates significance with the chi-square test. b: Kaplan-Meier analysis of the achievement of a MMR. The figure represents the probability to achieve a MMR (in %) as a function of the treatment duration (in months) for patients with the C/C genotype (continuous line) or patients with the C/T or T/T genotype (dotted line). c: cDNAs from 37 resistant patients were sequenced for both the BCR-ABL tyrosine kinase domain (TKD) and BIMEL coding region. The frequency of patients with non mutated or mutated TKD was plotted as a function of the c465C>T genotype. The numbers above the bars indicate the sample size. The p value was calculated using the Chi-square test.

Mentions: When the frequencies of the C/C, C/T and T/T genotypes in the responsive and resistant groups were compared to those of the local reference group (healthy controls) (Figure 1a), no significant difference was evidenced between the responder and reference groups. However, the distribution of the genotypes in the non responder group differed from that in the reference group (p =  0.016 using the chi square test) with an increased frequency of the T allele. This result was confirmed by the analysis of the non responder group compared to the local reference group using the SNPstats web tool showing an association of the genotype with the non responder phenotype in the dominant mode (OR, 4.13; CI, 1.49–11.45; p = 0.0049). We compared the c465C>T SNP genotype frequency in the patients obtaining a MMR in less than 18 months with those necessitating more time. Figure 2a, left panel, shows that the T allele was more frequently found in patients who do not reach a MMR in 18 months, i.e. patients in suboptimal response (chi square 3.88, p = 0.0488). The significance was better for a cut-off of 24 months to achieve a MMR (figure 2a, right panel, chi square 5.101, p = 0.0239). Moreover, a Kaplan-Meier analysis of the MMR frequency as a function of the treatment duration (figure 2b) confirmed that the presence of the T allele lengthened the time for achieving a MMR (p = 0.0407).


A single nucleotide polymorphism in cBIM is associated with a slower achievement of major molecular response in chronic myeloid leukaemia treated with imatinib.

Augis V, Airiau K, Josselin M, Turcq B, Mahon FX, Belloc F - PLoS ONE (2013)

Relation between the C/C or T/T plus C/T BIM genotypes and the achievement of MMR.a: cDNAs from 64 patients followed in the laboratory for their Bcr-Abl expression were sequenced for the BIMEL coding region. The number of patients achieving a MMR before or after 18 months (left panel) or 24 months (right panel) was plotted as a function of the c465C>T genotype: C/C (white bars) or C/T plus T/T (grey bars). p indicates significance with the chi-square test. b: Kaplan-Meier analysis of the achievement of a MMR. The figure represents the probability to achieve a MMR (in %) as a function of the treatment duration (in months) for patients with the C/C genotype (continuous line) or patients with the C/T or T/T genotype (dotted line). c: cDNAs from 37 resistant patients were sequenced for both the BCR-ABL tyrosine kinase domain (TKD) and BIMEL coding region. The frequency of patients with non mutated or mutated TKD was plotted as a function of the c465C>T genotype. The numbers above the bars indicate the sample size. The p value was calculated using the Chi-square test.
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Related In: Results  -  Collection

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pone-0078582-g002: Relation between the C/C or T/T plus C/T BIM genotypes and the achievement of MMR.a: cDNAs from 64 patients followed in the laboratory for their Bcr-Abl expression were sequenced for the BIMEL coding region. The number of patients achieving a MMR before or after 18 months (left panel) or 24 months (right panel) was plotted as a function of the c465C>T genotype: C/C (white bars) or C/T plus T/T (grey bars). p indicates significance with the chi-square test. b: Kaplan-Meier analysis of the achievement of a MMR. The figure represents the probability to achieve a MMR (in %) as a function of the treatment duration (in months) for patients with the C/C genotype (continuous line) or patients with the C/T or T/T genotype (dotted line). c: cDNAs from 37 resistant patients were sequenced for both the BCR-ABL tyrosine kinase domain (TKD) and BIMEL coding region. The frequency of patients with non mutated or mutated TKD was plotted as a function of the c465C>T genotype. The numbers above the bars indicate the sample size. The p value was calculated using the Chi-square test.
Mentions: When the frequencies of the C/C, C/T and T/T genotypes in the responsive and resistant groups were compared to those of the local reference group (healthy controls) (Figure 1a), no significant difference was evidenced between the responder and reference groups. However, the distribution of the genotypes in the non responder group differed from that in the reference group (p =  0.016 using the chi square test) with an increased frequency of the T allele. This result was confirmed by the analysis of the non responder group compared to the local reference group using the SNPstats web tool showing an association of the genotype with the non responder phenotype in the dominant mode (OR, 4.13; CI, 1.49–11.45; p = 0.0049). We compared the c465C>T SNP genotype frequency in the patients obtaining a MMR in less than 18 months with those necessitating more time. Figure 2a, left panel, shows that the T allele was more frequently found in patients who do not reach a MMR in 18 months, i.e. patients in suboptimal response (chi square 3.88, p = 0.0488). The significance was better for a cut-off of 24 months to achieve a MMR (figure 2a, right panel, chi square 5.101, p = 0.0239). Moreover, a Kaplan-Meier analysis of the MMR frequency as a function of the treatment duration (figure 2b) confirmed that the presence of the T allele lengthened the time for achieving a MMR (p = 0.0407).

Bottom Line: No mutation with amino-acid change was found in the BIM coding sequence.Similarly, this T allele was associated with the mutation frequency on the tyrosine kinase domain of BCR-ABL (p<0.001) and the presence of the T allele significantly lengthened the time to achieve a major molecular response (MMR).These results suggest that the analysis of the c465C>T SNP of BIM could be useful for predicting the outcome of imatinib-treated CML patients.

View Article: PubMed Central - PubMed

Affiliation: Université Bordeaux Segalen and INSERM U1035 Bordeaux, Bordeaux, France ; Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

ABSTRACT

Purpose: BIM is essential for the response to tyrosine-kinase inhibitors (TKI) in chronic myeloid leukaemia (CML) patients. Recently, a deletion polymorphism in intron 2 of the BIM gene was demonstrated to confer an intrinsic TKI resistance in Asian patients. The present study aimed at identifying mutations in the BIM sequence that could lead to imatinib resistance independently of BCR-ABL mutations.

Experimental design: BIM coding sequence analysis was performed in 72 imatinib-treated CML patients from a French population of our centre and in 29 healthy controls (reference population) as a case-control study. Real-time quantitative PCR (RT qPCR) was performed to assess Bim expression in our reference population.

Results: No mutation with amino-acid change was found in the BIM coding sequence. However, we observed a silent single nucleotide polymorphism (SNP) c465C>T (rs724710). A strong statistical link was found between the presence of the T allele and the high Sokal risk group (p = 0.0065). T allele frequency was higher in non responsive patients than in the reference population (p = 0.0049). Similarly, this T allele was associated with the mutation frequency on the tyrosine kinase domain of BCR-ABL (p<0.001) and the presence of the T allele significantly lengthened the time to achieve a major molecular response (MMR). Finally, the presence of the T allele was related to a decreased basal expression of the Bim mRNA in the circulating mononuclear cells of healthy controls.

Conclusion: These results suggest that the analysis of the c465C>T SNP of BIM could be useful for predicting the outcome of imatinib-treated CML patients.

Show MeSH
Related in: MedlinePlus