Association of promoter polymorphisms of Fas –FasL genes with development of Chronic Myeloid Leukemia

Abstract

Chronic myeloid leukemia (CML) is a monoclonal myeloproliferative disorder of hematopoietic stem cells (HSCs), characterized by reciprocal translocation, leading to the formation of BCR-ABL oncogene with constitutive tyrosine kinase (TK) activity. This oncogene is known to deregulate different downstream pathways which ultimately lead to cell proliferation, defective DNA repair, and inhibition of apoptosis. Fas (Fas cell surface death receptor) is a member of tumor necrosis factor (TNF) superfamily which interacts with its ligand, FasL, to initiate apoptosis. Promoter polymorphisms in Fas-FasL genes are known to influence the apoptotic signaling. Hence, the present study has been aimed to find out the association of the promoter polymorphisms in Fas and FasL genes with the development and progression of CML. Blood samples from 772 subjects (386 controls and 386 cases) were collected and genotyped for Fas-FasL gene polymorphisms through PCR-RFLP method. The association between SNPs and clinical outcome was analyzed using statistical softwares like SPSS version 20, SNPSTATs, and Haploview 2.1. The study revealed a significant association of Fas -670 G>A and FasL -844 T>C polymorphisms with the development of CML while Fas -670 AG was associated with accelerated phase. Combined risk analysis by taking the risk genotypes in cases and controls revealed a significant increase in CML risk with increase in number of risk genotypes (one risk genotype-OR 1.99 (1.44-2.76), p < 0.0001; two risk genotypes-OR 3.33 (1.91-5.81), p < 0.0001). Kaplan-Meier survival analysis of Fas -670 A>G and FasL -844 T>C showed reduced event-free survival in patients carrying the variant genotypes, Fas -670 GG, 32.363 ± 6.33, and FasL -844 CC, 33.489 ± 5.83, respectively. Our findings revealed a significant association of Fas -670 GG, FasL -844 TC, and CC genotypes with increased risk of CML.

A Cell’s Fate: An Overview of the Molecular Biology and Genetics of Apoptosis

“…Polymorphisms in FAS gene may decrease the apoptotic potential of the receptor, and have been associated with several illnesses, including cancer and musculoskeletal degenerative disorders [100,101]. Furthermore, there are studies demonstrating the association of FAS polymorphisms with the persistence of HTLV infections and its clinical manifestations, such as Adult T-Cell Leukemia (ATL) and HTLV-1-associated myelopathy (HAM) [102,103,104].…”

CD markers polymorphisms as prognostic biomarkers in hematological malignancies

“…Similarly, research has shown that CD95-670 G>A and CD178 −844 T>C SNPs are associated with the progression of CML toward accelerated and blast phases. 21 Given that CD95/CD178 is involved in the apoptosis process, these genetic changes could influence blast cells ’ resistance to apoptosis by affecting the expression and alteration of intracellular mechanisms. Indeed, this finding suggests that CD95/CD178 SNPs as potential prognostic factors provide for different degrees of disease progression in CML patients and are important in defining high-risk groups.…”

“…Although no association has been reported between CD95-1377 SNP and chronic myeloid leukemia (CML), research has shown that -670 GG and CD178 −844 TC SNPs are associated with increasing risk of CML and disease progression to accelerated and blast phases. 21 Unlike what observed in AML and CML, Tong et al . demonstrated that children carrying CD95 (-1377A, -670G) and CD178 (-844C) polymorphisms had reduced risk of acute lymphoblastic leukemia (ALL).…”

Impact of Fas/Fasl Gene Polymorphisms on Susceptibility Risk and Imatinib Mesylate Treatment Response in Chronic Myeloid Leukaemia Patients

“…However, the host genetic susceptibility factors favoring CML development have not been identified yet. Genetic variations such as functional single nucleotide polymorphisms (SNPs) in the apoptosis regulatory genes have been shown in the pathogenesis of malignant tumors and autoimmune diseases (Edathara et al, 2016).…”