Association of MDR1 gene polymorphism (G2677T) with chronic myeloid leukemia

Abstract Imatinib mesylate is the most opted drug used for treating ph+ve chronic myeloid leukemia (CML) patients. The up-regulation of drug transporters (ABCB1-ABCG2) is one of specific causes of Imatinib resistance. Imatinib (IM) is a substrate of the P-glycoprotein pump, which is encoded by MDR1/ABCB1 gene. Our main objective is to investigate the influence of MDR1 gene polymorphisms in CML patients. A total of 262 CML and 252 control samples were analysed for MDR1 gene (G2677T) polymorphism using PCR-RFLP technique. Genotype distribution revealed slight elevation of TT genotype frequency in CML patients (42.7%) compared to controls (38.5%). Patients in advanced phase had higher TT genotype frequency compared to patients in early phases. The frequency of heterozygous GT genotype was found to be increased in hematological poor responders (52.4%) compared to major responders (32.4%) and minor responders (30.0%). Interestingly, the frequencies of GG and GT genotypes were increased in cytogenetic poor responders with corresponding increase in G allele frequency (0.54) as compared to major responders (0.34). These results suggest that the 2677G allele with increased efflux of IM might be responsible for poor response in CML patients

<i style="mso-bidi-font-style:normal"><span style="font-size:11.0pt;font-family:"Times New Roman";mso-fareast-font-family: "Times New Roman";mso-bidi-font-family:Mangal;mso-ansi-language:EN-GB; mso-fareast-language:EN-US;mso-bidi-language:HI" lang="EN-GB">NRAS</span></i><span style="font-size:11.0pt;font-family:"Times New Roman";mso-fareast-font-family: "Times New Roman";mso-bidi-font-family:Mangal;mso-ansi-language:EN-GB; mso-fareast-language:EN-US;mso-bidi-language:HI" lang="EN-GB"> Mutations in <i style="mso-bidi-font-style:normal">de novo</i> acute leukemia: Prevalence and clinical significance</span>

207-210The activating mutations of the Ras gene or other abnormalities in Ras signaling pathway lead to uncontrolled growth factor-independent proliferation of hematopoietic progenitors. Oncogenic mutations in NRAS gene have been observed with variable prevalence in hematopoietic malignancies. In the present study, NRAS mutations were detected using bidirectional sequencing in 264 acute leukemia cases — 129 acute lymphocytic leukemia (ALL) and 135 acute myeloid leukemia (AML) and 245 age- and gender-matched controls. Missense mutation was observed only in the 12th codon of NRAS gene in 4.7% of AML and 3.16% of ALL cases. The presence of NRAS mutation did not significantly influence blast % and lactate dehydrogenase (LDH) levels in AML patients. When the data were analyzed with respect to clinical variables, the total leukocyte count was elevated for mutation positive group, compared to negative group. In AML patients with NRAS mutations, 60% failed to achieve complete remission (CR), as compared to 34.8% in mutation negative group. These results indicated that NRAS mutations might confer poor drug response. In AML, disease free survival (DFS) in NRAS mutation positive group was lesser, compared to mutation negative group (9.5 months <i style="mso-bidi-font-style: normal">vs. 11.68 months). In ALL patients, DFS of <i style="mso-bidi-font-style: normal">NRAS mutation positive group was lesser than mutation negative group (9.2 months vs. 27.5 months). The CR rate was also lower for mutation-positive patients group, compared to mutation-negative group. In conclusion, these results suggested that presence of NRAS mutation at 12th codon was associated with poor response and poorer DFS in both ALL and AML