Prognostic role of glutathione S-transferase polymorphisms in acute myeloid leukemia

Abstract

Glutathione S-transferases (GSTs) are phase II detoxification enzymes involved in the metabolism of carcinogens and anticancer drugs, known also to interact with kinase complexes during oxidative or chemical stress-induced apoptosis. We were interested whether their polymorphic variants may account for differences in outcome of patients with acute myeloid leukemia (AML) following chemotherapy. We studied the prognostic role of polymorphisms in three GST genes (GSTP1/M1/T1) in a large patient cohort of the German Austrian Acute Myeloid Leukemia Study Group, treated according to prospective multicenter clinical trials (AML HD98A: 254 patients; AML HD98-B: 100 patients), with a median follow-up of 46 months. Looking at short-term adverse drug reactions, homozygous carriers of the GSTP1*105 Val allele had a faster neutrophil and platelet recovery (P ¼ 0.002 and 0.02, respectively) and a reduced need of red cell and platelet transfusions (P ¼ 0.01 and 0.03, respectively). Response to induction chemotherapy did not vary according to GST polymorphisms. Multivariable Cox regression models revealed a significant better relapse-free (RFS) and overall survival for the GSTP1*105 Val (P ¼ 0.003 and 0.03, respectively), whereas GSTT1 and GSTM1 genotypes had no significant impact. The favorable impact of GSTP1*105 Val on RFS seems to be restricted to the subgroup of patients exhibiting a normal karyotype.

Meta-analysis study of glutathione-S-transferases (GSTM1,GSTP1, andGSTT1) gene polymorphisms and risk of acute myeloid leukemia

“…To view in colour online please go to: www.informaworld.com/glal were found to be associated with an increased risk of acute leukemia. Such individuals have an impaired ability to detoxify carcinogens, thus, carrying an increased risk of developing cancer [6][7][8][9]. Results of various studies have been contradictory with respect to the role of GST genes in AML [7,[11][12][13][14].…”

“…Similar mechanism has also been described for GSTT1 enzyme (GSTy subfamily) [5]. The gene coding for GSTP1 (GSTp subfamily), displays polymorphisms in its coding region at codons 105 (Ile!Val) and 114 (Ala!Val) which confer different catalytic activities based on the polymorphism [7][8][9].…”

Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia

“…Genetic polymorphisms in glutathione-S-transferases, such as GSTT1 and GSTM1 , have been widely studied for their associations with drug toxicity, drug response and disease risk in leukemia patients 29,39,42 . Notably, GSTM1 and GSTT1 deletions have been implicated in various phenotypes associated with leukemia including drug response 43 , busulfan pharmacokinetics 28 and disease risk 44 . Although we did not examine the effect of the GSTM1 deletion in this study, we identified several SNPs (genotyped and imputed) in the GSTM1 - GSTM5 locus (rs3754446, rs929166 and rs11101989) associated with DFS in individuals of European ancestry that have not been previously reported (Table 2, Figure 2b).…”

Involvement of Oxidative Stress in the Relapse of Acute Myeloid Leukemia

“…Disturbances to oxidative stress metabolism are commonly associated with tumor cells, and the level of oxidative stress among patients increases with disease severity and the accumulation of chromosomal aberrations (22,23). Leukemias originate from hematopoietic stem cells that lose the capacity to differentiate normally into mature blood cells (24,25).…”