Association of nitric oxide synthase 3 (NOS3) 894 G>T polymorphism with prognostic outcomes of anthracycline in Chinese patients with acute myeloid leukaemia

Abstract

The aim of the present study was to investigate the influence of the nitric oxide synthase 3 (NOS3) 894 G>T polymorphism on prognostic outcomes of anthracycline in Chinese patients with de novo intermediate-risk acute myeloid leukaemia (AML) and to examine the gene expression level in relation to genetic variation. In all, 225 Chinese patients with intermediate-risk AML (at the complete remission stage) treated with anthracycline were enrolled in the study. The 894 G>T polymorphism of the NOS3 gene was analysed by allele-specific matrix-assisted laser desorption ionization time-of-flight. Expression of NOS3 mRNA was tested in 72 patients of known genotype for NOS3 894 G>T. The clinical characteristics of these patients were obtained from medical records. Survival analysis showed that patients with AML (GG genotype) had a longer overall survival (OS; P = 0.006). After adjusting for age, gender, leucocyte count, haemoglobin level, platelet level, French, American and Britain (FAB) classification, lactate dehydrogenase levels, Eastern Cooperative Oncology Group Performance Status, nucleophosmin gene and fms-related tyrosine kinase 3 gene, multivariate survival analysis showed that the NOS3 894 G>T polymorphism appeared to be a predicting factor for OS (P = 0.014; hazard ratio = 1.856). However, no significant associations between the NOS3 894 G>T polymorphism and relapse-free survival and relapse in patients with AML were observed. Gene expression levels were significantly higher in patients with the GG genotype than in patients with the GT and TT genotypes (P = 0.033). The findings suggest that the NOS3 894 G>T variant may be a biomarker for the prediction of OS in Chinese patients with AML.

Exploring the mechanism of fraxetin against acute myeloid leukemia through cell experiments and network pharmacology

“…VEGFR-2 (KDR) is a key signal sensor for physiological and pathological angiogenesis, and a previous study showed that VEGFR-2 can directly or indirectly promote the proliferation of HL-60 cells, revealing that VEGFR-2 can be a target for drug intervention, inhibit tumor cell proliferation and promote apoptosis [ 36 ]. Endothelial nitric oxide synthase 3 (NOS3) is involved in regulating the production of ROS, which plays an important antitumor role in AML patients and can stimulate leukemia-related apoptotic pathways through oxidative stress, DNA damage, membrane damage, and lipid peroxidation; NOS3 is correlated with the overall survival of AML patients [ 37 ], and this finding is consistent with our survival analysis. VAV family genes (VAVs), which are located downstream of protein tyrosine kinases, including VAV1, VAV2, and VAV3, are signal transduction molecules that are regulated by tyrosine phosphorylation and are associated with the occurrence, progression, and prognosis of many cancers [ 38 ].…”

Influence of polymorphisms in anthracyclines metabolism genes in the standard induction chemotherapy of acute myeloid leukemia

“…The SNPs rs1799983 and rs2070744 of NOS3 have been associated with lower levels of the enzyme [13,27], as well as with lower survival [27]. In our cohort, opposing associations were observed in toxicity between both polymorphisms, not previously described.…”

“…The variant allele of NOS3 rs1799983 was associated with a protective effect against nephrotoxicity and thrombocytopenia, which had already been associated with a protective effect against cardiotoxicity [28]. In contrast, the minor allele of NOS3 rs2070744 increased hepatotoxicity and thrombocytopenia, probably related to lower activity of the enzyme [13,27].…”

“…Single-nucleotide polymorphisms (SNPs) in genes that encode enzymes of anthracyclines metabolic pathway have been previously studied [3,4], but only a few studies analyzed their impact on AML population and their findings were contradictory and inconclusive [6][7][8][9][10][11][12][13]. The main findings associated with polymorphisms in anthracycline enzymes were higher cardiotoxicity with CBR [14,15], lower with NQO1 [9,10,15] and lower survival with NOS3 [13,16], as well as no influence of AKR1C3 polymorphisms in cardiotoxicity was previously reported [6,7]. This study aims to elucidate the influence of the main polymorphisms that affect idarubicin metabolic pathway upon the effectiveness and safety of AML induction therapy.…”

A data-driven network model of primary myelofibrosis: transcriptional and post-transcriptional alterations in CD34+ cells

“…A recent study showed that NOS3 Glu298Asp polymorphism in homozygosis increased the risk of thrombosis in a cohort of patients with essential thrombocythemia or prefibrotic PMF. 56, 57 …”