Characterizing of Four Common BCR-ABL Kinase Domain Mutations (T315I, Y253H, M351T and E255K) in Iranian Chronic Myelogenous Leukemia Patients With Imatinib Resistance

Rejali, Leili; Poopak, Behzad; Hasanzad, Mandana; Sheikhsofla, Fatemeh; Varnoosfaderani, Ameneh Saadat; Safari, Nazila; Rabieipoor, Saghar

doi:10.17795/ijcp2334

Cited by 14 publications

(9 citation statements)

References 13 publications

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“…Mutations in the activation loop impair adopting the inactive conformation which is required for imatinib activity. Amino acid substitutions at seven residues [M244V, G250E, Y253F/H, E255K/V (P-loop), T315I (imatinib binding site), M351T, and F359V (catalytic domain)] account for 85% of all resistance associated mutations ( 36 , 45 ).…”

Section: Resultsmentioning

confidence: 99%

New Developments in Chronic Myeloid Leukemia: Implications for Therapy

Tabarestani

Movafagh

2016

Iran J Cancer Prev

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Context:Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by overproduction of immature and matured myeloid cells in the peripheral blood, bone marrow and spleen.Evidence Acquisition:A hallmark of CML is the presence of (9; 22) (q34; q11) reciprocal translocation, which is cytogenetically visible as Philadelphia chromosome (Ph) and results in the formation of BCR-ABL1 fusion protein. This fusion protein is a constitutively active tyrosine kinase which is necessary and sufficient for malignant transformation. The introduction of imatinib, a BCR-ABL1- targeting tyrosine kinase inhibitor (TKI) has revolutionized CML therapy. Subsequently, two other TKIs with increased activity against BCR-ABL1, dasatinib and nilotinib, were developed and approved for CML patients. Nevertheless, CML therapy faces major challenges.Results:The first is the development of resistance to BCR-ABL1 inhibitors in some patients, which can be due to BCR-ABL1 overexpression, differences in cellular drug influx and efflux, activation of alternative signaling pathways, or emergence of BCR-ABL1 kinase domain mutations during TKI treatment. The second is the limited efficiency of BCR-ABL1-TKIs in blast crisis (BC) CML. The third is the insensitivity of CML stem cells to BCR-ABL1 inhibitors. Conventional chemotherapeutics and BCR-ABL1 inhibitors which act by inhibiting cell proliferation and inducing apoptosis, are ineffective against quiescent CML stem cells.Conclusions:A better understanding of the mechanisms that underlie TKI resistance, progression to BC, genomic instability and stem cell quiescence is essential to develop curative strategies for patients with CML.

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Section: Resultsmentioning

confidence: 99%

New Developments in Chronic Myeloid Leukemia: Implications for Therapy

Tabarestani

Movafagh

2016

Iran J Cancer Prev

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“…There was a strong motivation for investigating the effect of this genetic variation as a possible source for many cancer predispositions ( 26 , 27 , 35 , 36 ). Experimental studies have shown that TGF-β was an important regulator of several cellular and molecular processes in the normal and malignant mammary epithelial cell lines ( 1 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of Two Common Promoter Polymorphisms of Transforming Growth Factor-β1 on Breast Cancer Risks in Ahvaz, West South of Iran

et al. 2016

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BackgroundTransforming growth factor-β1 (TGF-β1) has a critical role in breast cancer initiation and progression.ObjectivesWe have investigated the possible differences in two promoter polymorphisms (-509C/T and -800G/A) of TGF-β1 gene between breast cancer cases and controls.Patients and MethodsA total of 100 patients with confirmed breast cancer and 100 subjects without breast cancer was selected. Two promoter polymorphisms (-509C/T and -800G/A) of TGF-β1 gene were genotyped using PCR-based restriction fragment length polymorphism (RFLP) method.ResultsThe allele frequencies were 63% for C allele and 37% for T allele of SNP -509C/T and 66% for G allele and 34% for A allele of SNP -800G/A. Although no significant difference has observed between two groups, according to the genotype distribution, However, the TT genotype of -509 and AA genotype of -800 was significantly associated with breast cancer risk [odds ratio (OR) = 2.409; 95% confidence interval (CI) = 1.087 - 5.337, P = 0.030; and OR = 2.383; CI = 1.039 - 5.40, P = 0.040, respectively]. In addition, a multinomial logistic regression model shown, homozygous of -800 G/A (OR = 0.570; 95% CI = 0.362 - 0.896, P = 0.015); and HDL-C (OR = 0.935; 95% CI = 0.906 - 0.965, P < 0.001) were the selected variables associated with the presence of breast cancer. Haplotype analysis has shown no significant association between TGF-β1 haplotypes and breast cancer risk.ConclusionsOur results indicated that among two promoter polymorphisms of the TGF-β1gene, -800G/A compared to -509C/T is more associated with breast cancer.

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“…For example, the Bcr-Abl kinase inhibitor imatinib decreases mortality for Chronic Myeloid Leukemia (CML) by 80% (2, 3), but 22-41% of patients acquire resistance to imatinib (4). About 70% of relapsed patients harbor mutations in the Bcr-Abl kinase domain (5), in which more than a hundred different mutations have been identified (6)(7)(8). Some mutations are located near the imatinib binding site and cause resistance through altered interactions with the drug.…”

Section: Introductionmentioning

confidence: 99%

Mutation in Abl kinase with altered drug binding kinetics indicates a novel mechanism of imatinib resistance

Lyczek

Berger

Rangwala

et al. 2021

Preprint

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Protein kinase inhibitors are potent anti-cancer therapeutics. For example, the Bcr-Abl kinase inhibitor imatinib decreases mortality for Chronic Myeloid Leukemia (CML) by 80%, but 22-41% of patients acquire resistance to imatinib. About 70% of relapsed patients harbor mutations in the Bcr-Abl kinase domain, in which more than a hundred different mutations have been identified. Some mutations are located near the imatinib binding site and cause resistance through altered interactions with the drug. However, many resistance mutations are located far from the drug binding site and it remains unclear how these mutations confer resistance. Additionally, earlier studies on small sets of patient-derived imatinib resistance mutations indicated that some of these mutant proteins were in fact sensitive to imatinib in cellular and biochemical studies (10). Here, we surveyed the resistance of 94 patient-derived Abl kinase domain mutations annotated as disease-relevant or resistance-causing using an engagement assay in live cells. We found that only two-thirds of mutations weaken imatinib affinity by more than two-fold compared to Abl wild type. Surprisingly, one-third of mutations in Abl kinase domain still remain sensitive to imatinib and bind with similar or higher affinity than wild type. Intriguingly, we identified a clinical Abl mutation that binds imatinib with wild type-like affinity but dissociates from imatinib three times faster. Given the relevance of residence time for drug efficacy, mutations that alter binding kinetics could cause resistance in the non-equilibrium environment of the body where drug export and clearance play critical roles.

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Characterizing of Four Common BCR-ABL Kinase Domain Mutations (T315I, Y253H, M351T and E255K) in Iranian Chronic Myelogenous Leukemia Patients With Imatinib Resistance

Cited by 14 publications

References 13 publications

New Developments in Chronic Myeloid Leukemia: Implications for Therapy

New Developments in Chronic Myeloid Leukemia: Implications for Therapy

Effects of Two Common Promoter Polymorphisms of Transforming Growth Factor-β1 on Breast Cancer Risks in Ahvaz, West South of Iran

Mutation in Abl kinase with altered drug binding kinetics indicates a novel mechanism of imatinib resistance

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