INFLUX/EFFLUX TRANSPORTERS IN CHRONIC MYELOID LEUKEMIA: THE INFLUENCE OF GENETIC VARIANTS ON SUSCEPTIBILITY AND DRUG RESPONSE
Author(s): ,
Raquel Silva Alves
Affiliations:
Laboratory of Oncobiology and Hematology and University Clinic of Hematology,Faculty of Medicine, University of Coimbra (FMUC),Coimbra,Portugal;Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO),Faculty of Medicine, University of Coimbra (FMUC),Coimbra,Portugal;Center for Innovative Biomedicine and Biotechnology (CIBB),University
,
Ana Gonçalves
Affiliations:
Laboratory of Oncobiology and Hematology and University Clinic of Hematology,Faculty of Medicine, University of Coimbra (FMUC),Coimbra,Portugal;Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO),Faculty of Medicine, University of Coimbra (FMUC),Coimbra,Portugal;Center for Innovative Biomedicine and Biotechnology (CIBB),University
,
Joana Jorge
Affiliations:
Laboratory of Oncobiology and Hematology and University Clinic of Hematology,Faculty of Medicine, University of Coimbra (FMUC),Coimbra,Portugal;Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO),Faculty of Medicine, University of Coimbra (FMUC),Coimbra,Portugal;Center for Innovative Biomedicine and Biotechnology (CIBB),University
,
Gilberto Marques
Affiliations:
Clinical Pathology Service,Centro Hospitalar Universitário de Coimbra (CHUC),Coimbra,Portugal
,
André Barbosa Ribeiro
Affiliations:
Clinical Hematology Department,Centro Hospitalar Universitário de Coimbra (CHUC),Coimbra,Portugal;Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO),Faculty of Medicine, University of Coimbra (FMUC),Coimbra,Portugal
,
Rita Tenreiro
Affiliations:
Clinical Hematology Department,Centro Hospitalar Universitário de Coimbra (CHUC),Coimbra,Portugal
,
Margarida Coucelo
Affiliations:
Clinical Hematology Department,Centro Hospitalar Universitário de Coimbra (CHUC),Coimbra,Portugal;Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO),Faculty of Medicine, University of Coimbra (FMUC),Coimbra,Portugal
,
Joana Diamond
Affiliations:
Hemato-Oncology Laboratory,Instituto Português de Oncologia,Lisbon,Portugal
,
Amélia Pereira
Affiliations:
Medicine Department,Hospital Distrital da Figueira da Foz,Figueira da Foz,Portugal;Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO),Faculty of Medicine, University of Coimbra (FMUC),Coimbra,Portugal
,
Paulo Freitas-Tavares
Affiliations:
Clinical Hematology Department,Centro Hospitalar Universitário de Coimbra (CHUC),Coimbra,Portugal
,
António M. Almeida
Affiliations:
CIIS (Centro de Investigação Interdisciplinar em Saúde),Universidade Católica Portuguesa de Lisboa,Lisbon,Portugal;Hospital da Luz,Lisbon,Portugal
Ana Bela Sarmento-Ribeiro
Affiliations:
Laboratory of Oncobiology and Hematology and University Clinic of Hematology,Faculty of Medicine, University of Coimbra (FMUC),Coimbra,Portugal;Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO),Faculty of Medicine, University of Coimbra (FMUC),Coimbra,Portugal;Center for Innovative Biomedicine and Biotechnology (CIBB),University
EHA Library. Bela Sarmento-Ribeiro A. Jun 15, 2019; 266787; PS1170
Prof. Ana Bela Sarmento-Ribeiro
Prof. Ana Bela Sarmento-Ribeiro
Contributions
Abstract

Abstract: PS1170

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) is consider a clinical success, however TKI resistance constitute a clinical problem. Drug resistance can be associated with several mechanisms, which could alter drug target and/or impact drug access to target. TKI resistance mechanisms include mutations of the BCR-ABL gene and changes on influx and efflux transporters, which affect intracellular drug concentrations. Influx (like OCT1, OCTN2) and efflux transporters (as PgP, BCRP) comprise a variety of proteins express on cell and/or organelles membranes responsible for, respectively, the intrusion or extrusion of substrates, as nutrients, metabolic products, xenobiotics and chemotherapy. Since influx and efflux transporters mediate the intake and extrusion of TKIs, genetic variants on these genes could affect their function and modulate treatment response, as well as influence cancer development.

Aims
In this work, we explore the impact of genetic variability (as single nucleotide polymorphisms, SNPs) in genes related with drug transport (ABCB1, ABCG2, SLC22A1 and SLC22A5) on CML susceptibility, drug response and BCR-ABL mutation status.

Methods
In 198 CML patients and 404 controls, ten genetic variants in ABCB1, ABCG2, SLC22A1 and SLC22A5 were genotyped by tetra-primers-AMRS-PCR. The role of these SNPs in CML susceptibility and their association with clinical and laboratory characteristics as well as with therapy response was assessed by logistic regression analysis and/or by Fisher’s exact test, with p<0.05 considered as significant.

Results
Results showed that individuals with AA genotype of ABCB1 gene (rs1045642) are at higher risk of developing CML [Odds ratio (OR): 1.92; 95% confidence interval (CI): 1.134-3.281; P=0.015] while GG genotype is a protective factor [OR: 0.622; 95% CI: 0.438-0.884; P=0.008]. GG genotype of ABCG2 (rs2231142) was also associated with high risk for CML development, while allele T presents a protective action [OR: 0.589; 95% CI: 0.388-0.892; P=0.001]. In both SLC22A5 SNPs we observed that recessive alleles (G for rs274558 and C for rs2631365) confers protection, whereas individual with at least one recessive allele present lower risk to CML development. In our population we also observed an association between CML development and haplotypes as well as genotypic profile (GP). When we look for the influence of these SNPs on drug response, we found that GG genotype (rs2231142 ABCG2) is associated with 6x times more risk of TKI resistance [OR: 6.295; 95% CI: 1.445-27.413; P=0.0014] while allele T is correlated with a good drug response [OR: 0.176; 95% CI: 0.041-0.753; P=0.006]. We identify multiple GP that were associated with a high risk of resistance in CML, in particularly a complex GP with ten variants that reveal 21.45 higher risk of resistance [95% CI: 1.087-423.3; P=0.016]. BCR-ABL mutation is the predominant mechanism of TKI resistance and we found that CG carriers (rs683369 SLC22A1) presented 4.54 higher risk to develop mutations [95% CI: 1.701-12.11; P=0.003] and one influx GP was correlated with 13.58 times more probability of acquired BCR-ABL mutations [95% CI: 1.338-137.8; P=0.0254].

Conclusion

In conclusion, our results suggest that genetic variants of influx and efflux transporters genes seem to modulate drug response and are correlated with the acquisition of BCR-ABL mutations in CML patients. Additionally, these genetic polymorphisms might be involved in the susceptibility for CML development.

 

The work was supported by FMUC, CIMAGO (Project 18/12) and FCT (SFRH/BD/51994/2012).

Session topic: 7. Chronic myeloid leukemia - Biology & Translational Research

Keyword(s): Chronic myeloid leukemia

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