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This study aimed to screen for BCR-ABL kinase domain mutations in chronic myeloid leukemia patients experiencing resistance to the tyrosine kinase inhibitor imatinib. The researchers analyzed samples from 11 patients using reverse transcription polymerase chain reaction and DNA sequencing of the ABL kinase domain. Mutations were detected in 4 patients, including M351T, E355G, V379I, and E255K. Identifying such mutations can help guide treatment with second-generation tyrosine kinase inhibitors for patients resistant to imatinib.
This study aimed to screen for BCR-ABL kinase domain mutations in chronic myeloid leukemia patients experiencing resistance to the tyrosine kinase inhibitor imatinib. The researchers analyzed samples from 11 patients using reverse transcription polymerase chain reaction and DNA sequencing of the ABL kinase domain. Mutations were detected in 4 patients, including M351T, E355G, V379I, and E255K. Identifying such mutations can help guide treatment with second-generation tyrosine kinase inhibitors for patients resistant to imatinib.
This study aimed to screen for BCR-ABL kinase domain mutations in chronic myeloid leukemia patients experiencing resistance to the tyrosine kinase inhibitor imatinib. The researchers analyzed samples from 11 patients using reverse transcription polymerase chain reaction and DNA sequencing of the ABL kinase domain. Mutations were detected in 4 patients, including M351T, E355G, V379I, and E255K. Identifying such mutations can help guide treatment with second-generation tyrosine kinase inhibitors for patients resistant to imatinib.
Molecular Pathology,Department of Pathology and Microbiology, Aga Khan University Hospital Karachi. Introduction Chronic myelogenous Leukemia (CML Chromosomal translocation t(9;22) (q34;q11); yields Philadelphia chromosome.
Fusion gene BCR-ABL encodes constitutively active protein tyrosine kinase that promotes; Cell survival Cell proliferation Inhibition of apoptosis.
Chromosomal translocation t(9;22) Mechanism of action of BCR-ABL tyrosine kinase Mechanism of action of BCR-ABL tyrosine kinase inhibitor (Imatinib) Imatinib (STI571;Glevic )
Selective inhibitor of Tyrosine kinase
CHR 95% of patients CCyR 76% of patients 3 log in BCR-ABL.. 57% of patients CMR 4% of patients
Resistance to Imatinib 50% to 90% of CML patients acquired resistance to Imatinib due BCR ABL kinase domain point Mutations. Impair Imatinib Binding 4 region in Kinase domain where mutation can occur P loop Activation Loop Binding domain Catalytic Domain
Frequency of BCR ABL kinase Domain Mutation 100 different mutations have been identified 16 common mutations ---85% of all mutations F r e q u e n c y
Method for Mutation Analysis RNA Extraction Complimentary DNA formation RT-PCR DNA Sequencing DNA sequencing of ABL kinase Domain P loop Drug Binding loop Catalytic Domain Activation Loop 5TTAGGATCCTAGATTCGGAATCGTTGATCCTTATCACAGTCAGATATACTGGTAATCCATTCGATACGAGTAGATACAGA TCGTTAGGATCCTTTCGTTGATCCACTGGTAATCCATTCGATTAGATACAGATCCAGTCAGATATACTGGTAATCCAAGTCA GATATACTGCTGGTAATCCAAACCACAGTCAGATATACTGGTAATCCATTCGCTCACAGTCAGAGGGTACTGGTAATCCAT TCGATACGAGTAGATACAGATCGTTAGGATCCTTTCGTTGATCCTTCGTTGATCGTTGATCCACTGGTAATCATATGAATA3 716 bp BCR ABL M31T E355G E255K V3791
Results S # Patient Age Sex Mutation Detected Type of Mutation
1 Patient#1 40 M No 2 Patient#2 59 M Yes M351T 3 Patient#3 55 F No 4 Patient#4 30 M No 5 Patient#5 54 M No 6 Patient#6 31 M Yes E355G 7 Patient#7 60 F Yes V379I 8 Patient#8 55 F No 9 Patient#9 21 M No 10 Patient#10 97 F Yes E255K 11 Patient#11 66 M No Conclusion
BCR-ABL kinase domain mutations are associated with imatinib Resistance in CML patients. Timely identification of Imatinib resistance in CML patients help to set therapeutic strategies with 2 nd
generation TKIs. Direct DNA sequencing is a method of Choice in detection of ABL kinase Domain mutation. References Tensuz Tauchi ,Kanzuna OhyasShilei,Molecular mechanism of resistance of leukemia to Imatinib; Leukemia research 28SI(2004)S39-S45. C.Cameron Yin;Detection and Molecular monitoring of minimal residual disease in chronic myelogenous leukemia. Dragana Milojknovic; Mechanism of resistance to imatinib ad second generation tyrosine kinase in chronic myeloid leukemia ;Clin-Cancer-Res 2009;15(24);7519-27. Micheal J.,mauro;Defining and managing Imatinib resistance ;American Society of Hematology. Acknowledgment Faculty Members: Dr. Tariq Moatter Dr. Zahra Hasan