Abstract
Acute myeloid leukaemia (AML) is a heterogenous clonal hematopoietic malignancy primarily treated with combination of cytarabine (ara-C) and anthracyclines. Despite high remission rates, especially in younger patients, a vast majority of patients die due to relapse or chemotherapy/stem cell transplantation-related toxicity. The partial explanation for this grim clinical outcome lies in the patients' genetic variability. In this review, we will summarize how genetic polymorphisms of proteins, in metabolic paths of cytarabine and anthracyclines and proteins involved in regulation of apoptosis, influence efficacy and toxicity in the AML treatment.
Highlights
Acute myeloid leukaemia (AML) is a heterogenous clonal hematopoietic malignancy that arises from clonal expansion either of stem or early progenitor hematopoietic cells (1)
Variant alleles in CBR1 gene were associated with slower anthracycline metabolism and higher potential for cardiotoxicity, while variants in CBR3 gene were associated with increased anthracycline clearance
We have summarized results from studies that investigated how genetic variability in the genes involved in ara-C and anthracycline metabolic pathways, together with genes that regulate apoptosis, affects therapy response and survival in AML patients
Summary
Acute myeloid leukaemia (AML) is a heterogenous clonal hematopoietic malignancy that arises from clonal expansion either of stem or early progenitor hematopoietic cells (granulocyte, erythrocyte or megakaryocyte) (1). Longer event-free survival (EFS) was observed in AML patients with higher DCK mRNA expression in leukemic blasts. Wild-type single nucleotide polymorphisms (SNP) (201C>T and 360G>C) in DCK promoter regions, were associated with decreased mRNA expression, lower enzymatic activity and inferior 2-year EFS. Its increased expression was associated with resistance to ara-C (and other nucleoside analogues) and lower OS in AML patients (5,7). Leukemic cells of resistant AML patients harbour high levels of dCTP (5), which regulates ara-C effect by: DCK inactivation, CDA activation and by competing with ara-CTP for DNA incorporation (8). The most evaluated is the SLCO1B1 (solute carrier organic anion transporter family member) with variant allele C of 521T>C (rs4149056) which is associated with hepatotoxicity in AML patients (7). Wild types of SLC28A3, SLC25A37 and SLC22A2 polymorphisms have been associated with decreased DFS, but Bonferroni correction didn’t confirm these associations (7)
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