الفهرس | Only 14 pages are availabe for public view |
Abstract Chronic myelogenous leukemia (CML) is a myeloproliferative disorder originating from an abnormal hematopoietic stem cell and resulting in clonal proliferation of malignant myeloid progenitor cells. More than 95% of patients have a distinctive cytogenetic abnormality, the Philadelphia chromosome (Ph+). The Ph chromosome is derived from the translocation of DNA, between chromosomes 22 and 9. The translocation carries a specific fusion gene known as BCR-ABL, which encodes constitutively activated tyrosine kinases, whose activities interfere with cellular proliferation, cell death and interaction with the stromal microenvironment. Imatinib is a first generation TKI which is used widely as a treatment for CML. However, resistance to Imatinib was developed by many mechanisms. One of this mechanism of resistance is overexpression of efflux pump P-glycoprotein. In the current study, we focused on the ABCB1 (MDR1) genotype. We analyzed the 2 most relevant single nucleotide polymorphisms of MDR1 the G2677T and C3435T polymorphisms in 77 Egyptian patients having CML in the chronic phase and treated with imatinib. All patients were subjected to the following at diagnosis: complete history taking and clinical examination with special stress on the size of the spleen below the costal margin to calculate the Sokal score, complete blood picture, (RQ-PCR) for bcr-abl transcript level and PCR to detect the genotypes of G2677T and C3435T polymorphisms. All patients were followed up for 1 year. The following investigations were done at follow up: complete blood picture every 2 weeks until chr achieved then every 3 months, molecular analysis (RQ-PCR) for bcr-abl transcript level every 3 months, PCR to detect the genotypes of G2677T and C3435T polymorphisms after 12 months. In the present study, BCR-ABL transcripts level < 10% at 3 months was present in 34 patients, while those with BCR-ABL > 10% were 43 patients. After 12 months follow up, 35 patients have achieved MMR. Among those patients, 34 (97.7%) of them had BCR-ABL < 10 at 3 months of therapy. Concerning C3435T , the frequency of the CC, CT and TT genotypes in the responding group was (23.5%, 52.9% and 23.5% respectively) while in the non-responding group was (39.8%, 48.8% and 11.6% respectively). In the G2677T, the frequency of GG, GT and TT genotypes in the responding group was (17.6%, 58.8% and 23.5% respectively) while in the non-responding group was (37.2% ,58.1% and 4.7% respectively). The current study findings indicate that 2677G allele carriers might be at risk for imatinib resistance while the C3435T genotypes might not be a risk factor in the development of imatinib resistance. |