SLC29A1 single nucleotide polymorphisms as independent prognostic predictors for survival of patients with acute myeloid leukemia: an in vitro study

Wan, Heng; Zhu, Jianyi; Chen, Fangyuan; Xiao, Fei; Huang, Honghui; Han, Xiaofeng; Zhong, Lu; Zhong, Hua; Xu, Lan; Ni, Beiwen; Zhong, Jian‐Jiang

doi:10.1186/preaccept-1004172062141452

Cited by 7 publications

(6 citation statements)

References 39 publications

(43 reference statements)

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“…In addition, single nucleotide polymorphisms (SNPs) for nucleoside transporters exist that correlate both with toxicity and therapeutic efficacy of dF-dC in pancreatic cancer [ 82 ]. Similar roles of expression levels as well as polymorphisms have been reported for ara-C in the treatment of AML [ 83 , 84 , 85 , 86 , 87 ]. More recently, alternative transport mechanisms for ara-C and dF-dC, involving the SLC22 family, have been described, correlating with overall survival of AML patients treated with ara-C [ 282 ].…”

Section: Tumour-specific Resistance To Nucleobase/nucleoside Analosupporting

confidence: 71%

Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Tsesmetzis

Paulin

Rudd

et al. 2018

Cancers

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Antimetabolites, in particular nucleobase and nucleoside analogues, are cytotoxic drugs that, starting from the small field of paediatric oncology, in combination with other chemotherapeutics, have revolutionised clinical oncology and transformed cancer into a curable disease. However, even though combination chemotherapy, together with radiation, surgery and immunotherapy, can nowadays cure almost all types of cancer, we still fail to achieve this for a substantial proportion of patients. The understanding of differences in metabolism, pharmacokinetics, pharmacodynamics, and tumour biology between patients that can be cured and patients that cannot, builds the scientific basis for rational therapy improvements. Here, we summarise current knowledge of how tumour-specific and patient-specific factors can dictate resistance to nucleobase/nucleoside analogues, and which strategies of re-sensitisation exist. We revisit well-established hurdles to treatment efficacy, like the blood-brain barrier and reduced deoxycytidine kinase activity, but will also discuss the role of novel resistance factors, such as SAMHD1. A comprehensive appreciation of the complex mechanisms that underpin the failure of chemotherapy will hopefully inform future strategies of personalised medicine.

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Section: Tumour-specific Resistance To Nucleobase/nucleoside Analosupporting

confidence: 71%

Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Tsesmetzis

Paulin

Rudd

et al. 2018

Cancers

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“…Many studies also reported that functional abnormalities in SLC29A1were associated with AML resistance to Ara-C [ 25 , 26 ]. In previous studies, SLC29A1 genetic variants (such as rs693955, rs9394992, and rs324148) were associated with treatment outcomes in AML patients [ 27 , 28 ]. In terms of rs3734703, only two studies reported that AML patients with a high frequency of the major “C” allele (in other words, low MAF) of rs3734703 had a poor response to Ara-C-based therapy [ 29 ], while another study [ 30 ] did not find any rs3734703 associations with CR or RFS after induction chemotherapy with AML.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms at microRNA binding sites of Ara-C and anthracyclines-metabolic pathway genes are associated with outcome of acute myeloid leukemia patients

et al. 2017

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BackgroundGene polymorphisms at microRNA-binding sites (poly-miRTS) may affect gene transcription and expression through miRNA regulation, which is associated with cancer susceptibility, sensitivity to chemotherapy and prognosis. This study investigated the association between poly-miRTS of Ara-C/anthracycline metabolic pathways genes and the outcome of acute myeloid leukemia (AML) in Chinese patients after Ara-C-based chemotherapy.MethodsA total of 17 poly-miRTS were selected from the SNPinfo Web Server and genotyped in 206 Chinese Han non-FAB-M3 AML patients using the SEQUENOM Mass-ARRAY system.ResultsAmong these 17 poly-miRTS, five Ara-C metabolic gene single nucleotide polymorphisms (SNPs, NT5C2 rs10786736 and rs8139, SLC29A1 rs3734703, DCTD rs7278, and RRM1 rs1042919) were identified to significantly associate with complete AML remission and/or overall and relapse-free survival (OS and RFS, respectively), and four anthracycline-metabolic gene SNPs (ABCC1 rs3743527, rs212091, and rs212090 and CBR1 rs9024) were significantly associated with chemotherapy-related toxicities. Moreover, SLC29A1 rs3734703 was shown to associate with both chemotherapy response and survival (adjusted OR 2.561 in the overdominant model; adjusted HR 2.876 for OS and 2.357 for RFS in the dominant model).ConclusionsThe data from the current study demonstrated that the poly-miRTS of Ara-C/anthracyclines metabolic genes predicted the sensitivity and side effects of AML to Ara-C-based chemotherapy and patient survival. Further study will confirm them as biomarkers for AML patients after Ara-C-based chemotherapy.Electronic supplementary materialThe online version of this article (10.1186/s12967-017-1339-9) contains supplementary material, which is available to authorized users.

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“…It is the most common form of acute leukemia in adults and the second most common form of leukemia in children after acute lymphoblastic leukemia (ALL) [ 1 , 2 ]. Pediatric AML comprises up to 20% of all childhood leukemia and the mechanism behind poor survival of acute myeloid leukemia (AML) patients remains unclear [ 3 ]. Several novel recurrent mutations have been found to involve epigenetically regulated genes in AML, including DNMT3A [ 4 , 5 ], TET2 [ 6 , 7 ], and IDH1/2 [ 8 ], which are involved in the regulation of DNA methylation, and EZH2 [ 9 , 10 ] and ASXL-1 [ 11 ], which are implicated in the regulation of histones [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Early B-cell factor 3 (EBF3) is a novel tumor suppressor gene with promoter hypermethylation in pediatric acute myeloid leukemia

Tao

et al. 2015

J Exp Clin Cancer Res

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BackgroundPediatric acute myeloid leukemia (AML) comprises up to 20% of all childhood leukemia. Recent research shows that aberrant DNA methylation patterning may play a role in leukemogenesis. The epigenetic silencing of the EBF3 locus is very frequent in glioblastoma. However, the expression profiles and molecular function of EBF3 in pediatric AML is still unclear.MethodsTwelve human acute leukemia cell lines, 105 pediatric AML samples and 30 normal bone marrow/idiopathic thrombocytopenic purpura (NBM/ITP) control samples were analyzed. Transcriptional level of EBF3 was evaluated by semi-quantitative and real-time PCR. EBF3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BGS). The molecular mechanism of EBF3 was investigated by apoptosis assays and PCR array analysis.ResultsEBF3 promoter was hypermethylated in 10/12 leukemia cell lines. Aberrant EBF3 methylation was observed in 42.9% (45/105) of the pediatric AML samples using MSP analysis, and the BGS results confirmed promoter methylation. EBF3 expression was decreased in the AML samples compared with control. Methylated samples revealed similar survival outcomes by Kaplan-Meier survival analysis. EBF3 overexpression significantly inhibited cell proliferation and increased apoptosis. Real-time PCR array analysis revealed 93 dysregulated genes possibly implicated in the apoptosis of EBF3-induced AML cells.ConclusionIn this study, we firstly identified epigenetic inactivation of EBF3 in both AML cell lines and pediatric AML samples for the first time. Our findings also showed for the first time that transcriptional overexpression of EBF3 could inhibit proliferation and induce apoptosis in AML cells. We identified 93 dysregulated apoptosis-related genes in EBF3-overexpressing, including DCC, AIFM2 and DAPK1. Most of these genes have never been related with EBF3 over expression. These results may provide new insights into the molecular mechanism of EBF3-induced apoptosis; however, further research will be required to determine the underlying details.Our findings suggest that EBF3 may act as a putative tumor suppressor gene in pediatric AML.

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SLC29A1 single nucleotide polymorphisms as independent prognostic predictors for survival of patients with acute myeloid leukemia: an in vitro study

Abstract: Background: The mechanism behind poor survival of acute myeloid leukemia (AML) patients with 1-barabinofuranosylcytosine (Ara-C) based treatment remains unclear. This study aimed to assess the pharmacogenomic effects of Ara-C metabolic pathway in patients with AML.

Cited by 7 publications

References 39 publications

Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Polymorphisms at microRNA binding sites of Ara-C and anthracyclines-metabolic pathway genes are associated with outcome of acute myeloid leukemia patients

Early B-cell factor 3 (EBF3) is a novel tumor suppressor gene with promoter hypermethylation in pediatric acute myeloid leukemia

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