SLC29A1 single nucleotide polymorphisms as independent prognostic predictors for survival of patients with acute myeloid leukemia: an in vitro study
- Haixia Wan†1,
- Jianyi Zhu†1,
- Fangyuan Chen1Email author,
- Fei Xiao1,
- Honghui Huang1,
- Xiaofeng Han1,
- Lu Zhong1,
- Hua Zhong1,
- Lan Xu1,
- Beiwen Ni1 and
- Jihua Zhong1
© Wan et al.; licensee BioMed Central Ltd. 2014
Received: 2 September 2014
Accepted: 20 October 2014
Published: 15 November 2014
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.
The genotypes of 19 single nucleotide polymorphisms (SNPs) of DCK, CDA and SLC29A1from 100 AML patients treated with Ara-C were examined. All the SNPs were screened with ligase detection reaction assay. The transcription analysis of genes was examined by quantitative real time polymerase chain reaction. The association between clinical outcome and gene variants was evaluated by Kaplan-Meier method.
Genotypes of rs9394992 and rs324148 for SLC29A1 in remission patients were significantly different from those in relapsed ones. Post-induction overall survival (OS) significantly decreased in patients with the CC genotype of rs324148 compared with CT and TT genotypes (hazard ratio [HR] = 2.997 [95% confidence interval (CI): 1.71-5.27]). As compared with CT and TT genotype, patients with the CC genotype of rs9394992 had longer survival time (HR = 0.25 [95% CI: 0.075-0.81]; HR = 0.43 [95% CI: 0.24-0.78]) and longer disease-free survival (DFS) (HR = 0.52 [95% CI: 0.29-0.93]; HR = 0.15 [95% CI: 0.05-0.47]) as well As compared with CT and TT genotype, patients with the CC genotype of rs324148 had shorter DFS (HR = 3.18 [95% CI: 1.76-5.76]). Additionally, patients with adverse karyotypes had shorter DFS (HR = 0.17 [95% CI: 0.05-0.54]) and OS (HR = 0.18 [95% CI: 0.05-0.68]).
AML patients with low activity of SLC29A1 genotype have shorter DFS and OS in Ara-C based therapy. Genotypes of rs9394992 and rs324148 may be independent prognostic predictors for the survival of AML patients.
Acute myeloid leukemia (AML), a heterogeneous disease with various clinical presentations, can be treated with 1-barabinofuranosylcytosine (Ara-C) or Ara-C combined with anthrocycline –. Despite the big progress in respect to the improved remission rate of a majority of patients (50-60%) under 60 years old, the outcome of Ara-C based treatment is still unsatisfactory as 30-80% of patients relapse eventually after remission . Besides, long-term survival rates continue to be around 30% to 40% for adults, and treatment of patients with relapsed or refractory AML with Ara-C based chemotherapy is unable to produce a prolonged leukemia-free survival in most patients ,. The mechanism behind poor survival of AML patients with Ara-C based treatment still remains unclear.
Genes involved in Ara-C transport and metabolism, and the potential mechanisms of Ara-C resistance, are investigated in the previous studies. DCK can be inhibited by increased dCTP pool through a negative feedback, and increased CDA function leads to increase in the deamination of Ara-C to AraU –. Decreased Ara-C transport over the cell membrane into the cytoplasm , or inactivation of DCK , can both offset the cytotoxic function of Ara-C. Our previous study showed continuous exposure to Ara-C could induce drug resistance with decreased transcription level of DCK and SLC29A1 as well as elevated mRNA expression of CDA (data not shown). Genetic variations, particularly SNPs, have been identified in these genes involved in Ara-C transport and metabolism –. Both in vivo and in vitro studies demonstrated that the activities of these enzymes are correlated with polymorphic gene variations ,, and some of these SNPs are even highly correlated with treatment response and survival of AML patients with Ara-C based chemotherapy –. Previous study found that rs329491 of SLC29A1 maybe a favorable survival factor for patients with pancreatic cancer . Another study also showed that rs9394992 may be associated with the survival of patients with non-small cell lung cancer . However, none of these SNPs have been reported in leukemia patients.
To investigate the possible involvement of genes correlating with Ara-C transport and metabolism in patients with chemotherapy-resistant AML, we assessed the pharmacogenomic effects of Ara-C metabolic/transport pathway in AML in this study.
Patients’ characteristics and treatment outcomes
Characteristics of AML patients
Bone marrow blasts (%)
WBC count (x109/L)
Transcription level of genes involving in Ara-C transport and metabolism
Genotype frequencies of DCK, CDA and SLC29A1 polymorphisms
Characteristics of 19 SNPs
ref SNP ID
NM_000788.2:c.-201C > T
NM_000788.2:c.207 + 9846A > G
NM_000788.2:c.757-1205C > T
NM_000788.2:c.165C > T
NM_000788.2:c.207 + 11338A > G
NM_000788.2:c.666-346 T > C
NM_000788.2:c.92-1110 T > C
NM_000788.2:c.266 + 3264A > G
NM_000788.2:c.267-4159C > T
NM_000788.2:c.267-4087G > A
NM_000788.2:c.154 + 1015A > G
NM_000788.2:c.155-7161G > A
NM_000788.2:c.266 + 1809G > A
NM_000788.2:c.266 + 2751G > A
NM_000788.2:c.208G > A
NM_001078174.1:c.30-549 T > C
NM_001078174.1:c.1260-201A > G
NM_001078174.1:c.29 + 913C > T
NM_001078174.1:c.-54-3077A > G
Impact of SNP genotypes on treatment response
Impact of genotypes of rs9394992 and rs324148 on SLC29A1 transcription
To further investigate the effect of different genotypes of polymorphic varies on the transcription of SLC29A1, we evaluated the mRNA expression of the rs9394992 and rs324148 of SLC29A1 in AML patients. Higher mRNA expression of genotype TT was observed in rs324148, as compared to that of genotype CC (P < 0.01). Higher expression of genotype CC was observed in rs9394992 compared with genotype CT and TT (P < 0.01) (Figure 4c), which indicated that SNPs might modify Ara-C toxicity through transcription regulation.
The effect of SNPs on Ara-C based treatment outcomes
The CC genotype of SNP16 was significantly associated with shorter DFS compared to the CT and TT genotypes (HR = 3.18 [95% CI: 1.76-5.76], P = 0.0001) (Figure 5b). Genotype of CC of SNP18 was associated with longer DFS compared to CT (HR = 0.52 [95% CI: 0.29-0.93], P = 0.03) or TT genotypes (HR = 0.15 [95% CI: 0.05- 0.47], P = 0.001) (Figure 5d). This association was more significant in patients with both genotype CC of rs324148 and genotype CT + TT of rs9394992 (Figure 6b).
Impact of other variables on Ara-C based treatment outcomes
It has been demonstrated in the previous studies that cytogenetics and molecular abnormalities were independent predictors for the prognosis of AML patients –. However, in our study, adverse cytogenetic abnormalities only accounted for 8.6% (n = 93) of patients. The majority of patients was with intermediate and favorable cytogenetics and showed no difference in survival. As Ara-C forms the backbone of the treatment regimen, understanding the contribution of pharmacogenetics to Ara-C response may help dissection of AML with distinct prognosis, so as to individualize chemotherapy and potentially improve the outcomes of AML patients.
In our study, we observed single SNP and SNP-SNP interactions in the Ara-C transport pathway, which could account for the interpatient variability of treatment outcomes in AML patients. When tested independently, both SNP rs324148 and rs9394992 in the SLC29A1gene contributed to Ara-C resistance in patients with AML who received Ara-C based treatment, and they were also significant prognostic factors for survival of these patients. The genotypes of these two SNPs showed various mRNA expressions, which may be responsible for varied response to Ara-C treatment. Although the SNPs in our study located in the intron region of SLC29A1, they affected mRNA expression, which might be due to direct regulation of transcription by altering RNA elongation, splicing or maturation –.
SLC29A1 was expressed in 83% of the AML patients . The results of the studies on the association between SLC29A1 of human AML blasts and clinical drug response were not consistent. Previous data showed that there was no association between SLC29A1 and Ara-C sensitivity . However, some studies demonstrated close correlation of SLC29A1 with Ara-C resistance, treatment response and survival of patients with AML. The inhibition of SLC29A1 expression may induce Ara-C resistance; thereby reduce the overall survival of patients with AML ,. FLT3-ITD indicates poor prognosis in AML, and one of the mechanisms involved was to suppress the expression of SLC29A1 to induce Ara-C resistance in AML patients .
Besides SLC29A1, other genes or mechanisms may be responsible for Ara-C resistance. Previous in-vitro studies showed that the expression of DCK was correlated with cellular sensitivity to Ara-C, while decreased DCK activity was observed in Ara-C resistant cell lines ,,. DCK and 5-NT mRNA expression in leukaemic blasts at diagnosis was correlated with clinical outcome , although no alterations in DCK expression and/or activity were observed in resistant and sensitive AML patients . Alternatively spliced forms of DCK with reduced activity were found in Ara-C resistant blasts ,, suggesting that DCK may contribute to Ara-C resistance. Our study detected higher DCK expression in leukemia blast in remission patients, but failed to find any difference of polymorphisms between remission and relapsed patients. CDA may be another factor for Ara-C resistance. Elevated CDA activity was correlated with Ara-C resistance ,. CDA could be an independent prognostic parameter for survival in AML patients treated with Ara-C . Other genes, including 5-NT and RRM1 or RRM2, were also found to be involved in Ara-C resistance ,,,,.
Our study failed to detect the activity of SLC29A1A in AML patients, in whom we inferred SLC29A1 activity from genotype or mRNA expression correlated with Ara-C sensitivity . In addition, we could not differentiate the difference of survival between different genotype combinations of rs9394992 and rs324148, which might be due to other SNPs. Studies showed DCK rs4694362 (CC genotype) may be a poor prognostic factor for the OS of AML patients. SLC29A1 rs3734703 (AA or AC genotype) together with TYMS rs2612100 (AA genotype) were associated with shorter relapse free survival (RFS) . Polymorphisms within the CDD gene also had an impact on the survival of patients with AML . In AML patients without FLT3-ITD, variant allele of rs10883841 in 5-NT was associated with shorter survival . In addition, polymorphisms of other genes were also identified to be responsible for the prognosis of AML patients ,. Therefore, more parameters need to be included for better prognostic stratification.
Interestingly, our previous study found that fludarabine (Flu) may restore the Ara-C sensitivity in AML blasts (Additional file 1a,b) and increase the cytoxicity of Ara-C (Additional file 1a), partially by increasing the mRNA expression of DCK, SLC29A1, and decreasing mRNA expression of CDA, RRM1 and RRM2 (Additional file 1c). Clinical studies also suggested that Flu may have a beneficial impact on the antileukemic efficacy of Ara-C-based salvage therapy for relapsed and refractory AML ,.
In conclusion, cytogenetics might not be enough to predict the prognosis of AML. Polymorphisms in genes related to its Ara-C metabolism may serve as biomarkers for Ara-C sensitivity, treatment response, and prognostic markers in AML, thus individualize chemotherapy and potentially improve outcomes of AML patients.
Materials and methods
From July 2004 to July 2009, 100 Asian Chinese adults with de novo AML other than M3 were randomized to receive low-dose cytarabine (100 mg/m2 intravenously for 24 hours, given on day 1–7; n = 100) plus daunorubicin (45 mg/m2 intravenously on day 1–3) or indarubicin (10 mg/m2 intravenously on day 1–3). High-dose cytarabine (2 g/m2 intravenously over 3 hours, given every 12 hours on day 1–3; n = 27) was administered to patients for second cycle induction (n = 4) or for consolidation. All patients were chemonaive at enrollment with leukemia blasts > 70% in the bone marrow. Meanwhile, 100 healthy controls (media age: 46 years, range 14–84 years; n = 50 for male) were also included.
Subjects diagnosed with any other cancers or perniciously administered cytotoxic drugs or radiation was excluded. Primary bone marrow samples were collected after informed consent was obtained from patients or their guardians, in accordance with the Declaration of Helsinki. This study was approved by the institutional research board at Renji Hospital, Shanghai.
SNP selection and genotyping
Three cytarabine transport and metabolism genes including SLC29A1, DCK and CDA were reported to potentially involve in the response to cytarabine. Based on the database from NCBI (http://www.ncbi.nlm.nih.gov/) and International Hap-Map project (http://hapmap.ncbi.nlm.nih.gov/), 19 candidate SNPs in these genes were initially selected.
Mononuclear cells (MNCs) were purified with Ficoll. Genomic DNA was extracted from MNC samples using standard methods recommended and normalized to 1 μg/μl. Quality and quantity of the extracted DNA was checked on a Nanodrop ND-1000 UV–vis Spectrophotometer (NanoDrop Technologies, Wilmington, DE, USA) by spectral absorption scans from 230 to 350 nm. Genotyping for the all genes’ polymorphism was performed using ligase detection reaction (LDR) assay following the manufacturer’s instructions. Gene-specific polymerase chain reaction (PCR) primers and fluorogenic probes for allelic discrimination were supplied by Shanghai Generay Biotech. PCR cycling and ligation reactions were performed in a GeneAmp PCR System 9700 (Applied Biosystems, Foster City, CA) according to the conditions specified by the manufacturer. Ligation products were analyzed using ABI PRISM® 377 DNA Sequencer (Applied Biosystems, Foster City, CA). Genotyping results were duplicated in 15% of samples with 100% concordance between repeats.
Genomic DNA was extracted from peripheral blood samples of 100 healthy donors using QIAamp blood DNA isolation kits (Qiagen Sciences, Maryland, USA) as per the manufacturer’s protocol. Genotyping was performed as described for the patient population.
Real time PCR
0.5 ± 106 leukemia cells were harvested, and total RNA was extracted using the RNeasy Plus Mini kit (QIAGEN, GmbH, Hilden, Germany) following the manufacturer’s protocol. RNA quality and quantification were assessed using the optical spectrometry 260/280 nm ratio. Subsequently, mRNA was reverse transcribed to cDNA using Applied Biosystems High Capacity Reverse Transcription kit (Applied Biosystems, Foster City, CA). Quantitative RT-PCR was performed for DCK, CDA and SLC, with β-actin as the internal control, using SYBR Premix Ex Taqs (TaKaRa, Kyoto, Japan) on the Roche LightCycler® 480 system (Roche, Mannheim, Germany). Total reaction was carried out in 10 μl volume, which consisted of 5 μl SYBR Premix Ex Taqs Master Mix, 0.1 μl primers (final of 10 nM forward and reverse primers), and 4 μl water, along with 0.8 μl cDNA. The fast thermocycler parameters were: 95°C for 10 seconds, and 40 cycles of 95°C for 5 second then 60°C for 30 seconds and 78°C for 1 second. The qRT-PCR was run in triplicate and individual samples run in triplicate on the RT-PCR plates. Primers were supplied by Sangon Biotech in shanghai.
Disease-free survival (DFS) was defined as time from remission to failure at the end of two courses, relapse or death of any cause. Overall survival (OS) was defined as time from study entry to death of any cause. Complete remission (CR) after induction chemotherapy was defined as: (1) normal values for absolute neutrophil (>1000/mcL) and platelet counts (≥100,000/mcL) independent of transfusion; (2) less than 5% of blast cells, no blasts with Auer rods on bone marrow examination; (3) absence of extramedullary leukemia. Partial remission (PR) was defined as decrease of at least 50% in the percentage of blasts to 5-25% in the bone marrow aspirate and the normalization of blood counts. CR and PR were defined as overall remission. Relapse was defined as marrow infiltration by more than 5% of blast cells in previous normal bone marrow or evidence of extramedullary leukemia. Patients lost to follow-up, survived (for OS) or maintained remission (for DFS) up to the end of the research were censored at their date of last known contact.
Differences of the frequencies between genotypes and alleles in AML (remission and relapsed) patients and normal controls were evaluated using Chi-square test and Fisher’s exact test when data were sparse. The expression of mRNA between different genotypes of SNPs or between different genes was analyzed with t test. DFS and OS were calculated using Kaplan-Meier estimates. A cut off P-value of 0.05 was adopted for all statistical analyses. Statistical significance is represented by the two-tailed P values.
HW performed the research, analyzed the data, and wrote the manuscript; FC designed and supervised the research; JZ, FX and HH collected clinical samples and data; JZ was responsible for part of the experiment. All authors read and approved the final manuscript.
The authors appreciated the contribution from the members of Leukemia Research Institute in Ren Ji Hospital. The study was partially supported by Science and Technology Commission of Shanghai Municipality (no.14411950704), Shanghai Jiaotong University as well as the Science and Technology Research Fund (2008XJ015).
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