scholarly journals MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia

Genes ◽  
2019 ◽  
Vol 10 (4) ◽  
pp. 319 ◽  
Author(s):  
Bhise ◽  
Elsayed ◽  
Cao ◽  
Pounds ◽  
Lamba
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Metabolic Pathway ◽  
Myeloid Leukemia ◽  
Nucleoside Analogs ◽  
Nucleoside Analog ◽  
Interindividual Variation ◽  
Expression Levels ◽  
Gene Expression Levels ◽  
Acute Myeloid

Nucleoside analog, cytarabine (ara-C) is the mainstay of acute myeloid leukemia (AML) chemotherapy. Cytarabine and other nucleoside analogs require activation to the triphosphate form (ara-CTP). Intracellular ara-CTP levels demonstrate significant inter-patient variation and have been related to therapeutic response in AML patients. Inter-patient variation in expression levels of drug transporters or enzymes involved in their activation or inactivation of cytarabine and other analogs is a prime mechanism contributing to development of drug resistance. Since microRNAs (miRNAs) are known to regulate gene-expression, the aim of this study was to identify miRNAs involved in regulation of messenger RNA expression levels of cytarabine pathway genes. We evaluated miRNA and gene-expression levels of cytarabine metabolic pathway genes in 8 AML cell lines and The Cancer Genome Atlas (TCGA) data base. Using correlation analysis and functional validation experiments, our data demonstrates that miR-34a-5p and miR-24-3p regulate DCK, an enzyme involved in activation of cytarabine and DCDT, an enzyme involved in metabolic inactivation of cytarabine expression, respectively. Further our results from gel shift assays confirmed binding of these mRNA-miRNA pairs. Our results show miRNA mediated regulation of gene expression levels of nucleoside metabolic pathway genes can impact interindividual variation in expression levels which in turn may influence treatment outcomes.

Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. 5905-5913 ◽  
Author(s):  
Anna Staffas ◽  
Meena Kanduri ◽  
Randi Hovland ◽  
Richard Rosenquist ◽  
Hans Beier Ommen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Markers ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
Expression Levels ◽  
Pediatric Aml ◽  
Gene Expression Levels ◽  
Acute Myeloid

Abstract Mutation status of FLT3, NPM1, CEBPA, and WT1 genes and gene expression levels of ERG, MN1, BAALC, FLT3, and WT1 have been identified as possible prognostic markers in acute myeloid leukemia (AML). We have performed a thorough prognostic evaluation of these genetic markers in patients with pediatric AML enrolled in the Nordic Society of Pediatric Hematology and Oncology (NOPHO) 1993 or NOPHO 2004 protocols. Mutation status and expression levels were analyzed in 185 and 149 patients, respectively. Presence of FLT3-internal tandem duplication (ITD) was associated with significantly inferior event-free survival (EFS), whereas presence of an NPM1 mutation in the absence of FLT3-ITD correlated with significantly improved EFS. Furthermore, high levels of ERG and BAALC transcripts were associated with inferior EFS. No significant correlation with survival was seen for mutations in CEBPA and WT1 or with gene expression levels of MN1, FLT3, and WT1. In multivariate analysis, the presence of FLT3-ITD and high BAALC expression were identified as independent prognostic markers of inferior EFS. We conclude that analysis of the mutational status of FLT3 and NPM1 at diagnosis is important for prognostic stratification of patients with pediatric AML and that determination of the BAALC gene expression level can add valuable information.

Imprinted Non-Coding RNA Genes, H19 and ZNF215, Are Potential Markers For Two-Year Survival For Acute Myeloid Leukemia Patients With Normal and Abnormal Karyotypes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2605-2605
Author(s):  
Ming-Yu Yang ◽  
Jan-Gowth Chang ◽  
I-Ya Chen ◽  
Pai-Mei Lin ◽  
Hui-Hua Hsiao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Large Scale ◽  
Conflicts Of Interest ◽  
Linear Regression Analysis ◽  
Altered Expression ◽  
Expression Levels ◽  
Confident Interval ◽  
Acute Myeloid

Abstract Studies in large-scale genome sequencing have shown that only 2% of the mammalian genome encodes mRNAs, but the most part is transcribed as long and short non-coding RNAs (ncRNAs). The ncRNAs with gene regulatory functions are starting to be seen as a common feature of mammalian gene regulation. Genomic imprinting is a form of epigenetic regulation and imprinted genes are silenced in a parental-specific manner. Although the exact mechanism how imprinted ncRNA regulates gene expression remains largely unknown, it is general accepted that imprinted ncRNAs binds to chromatin modifying complexes, such as PRC2, TRX, and G9a, and generates specific silencing of genomic loci both in cis and trans. Imprinting is associated with many human diseases or syndromes (e.g. Prader-Willi, Angelman, Beckwith-Wiedemann, Retts, and Silver-Russell syndromes) and various cancers (e.g. breast, prostate, and colorectal cancers), but its role in leukemogenesis remain elusive. In this present study, the expression of a panel of 24 human imprinted ncRNA genes (AMPD3, C15orf2, COPG2, CPA4, GABRB3, H19, IGF2, IMPACT, INPP5F, L3MBTL, NR3251, NR3252, PEG3-AS, PPP1R9A, PRIM2, RASGRF1, RTL1, SFMBT2, SLC22A3, SNURF, TCEB3C, TSPAN32, ZNF215, ZNF264) and a panel of 66 human histone modifying enzymes (HME) genes was investigated in 68 newly-diagnosed acute myeloid leukemia patients with chromosome normal (AML-CN), 115 AML patients with chromosome abnormal (AML-CA), and 85 healthy individuals using real-time quantitative RT-PCR. Altered expression of 9 imprinted ncRNA genes (C15orf2, COPG2, H19, IGF2, IMPACT, PEG3-AS, PRIM2, SLC22A3, ZNF215) and 16 HME genes were observed. In AML-CN, patients’ survival days are correlated with the expression levels of H19 (p < 0.01), IMPACT (p < 0.05), DNMT3L (p < 0.05) and AURORA (p < 0.01). In AML-CA, patients’ survival days are correlated with the expression levels of PGE3-AS (p < 0.01), PRIM2 (p < 0.01), SLC22A3 (p < 0.05), and ZNF215 (p < 0.01). Multiple linear regression analysis further revealed the expression level of H19 and ZNF215 can be used as predictors for 2-year survival for AML-CN patients (p = 0.002) and AML-CA patients (p = 0.040), respectively. Cox proportional hazard model was used to analyze the hazard ratio (HR) for H19 (HR=0.868, 95.0% Confident Interval: 0.797-0.945, p = 0.001) and ZNF215 (HR=0.904, 95.0% Confident Interval: 0.821-0.995, p =0.040). In addition to survival, analysis has also been performed to correlate patients’ clinical parameters and expression levels of these altered genes and to correlate the expression levels between imprinted ncRNA genes and HME genes (results will be presented at the meeting). From our preliminary results, it is reasonable to hypothesize that loss imprinting of imprinted ncRNA is critical for the leukemogenesis of AML and under CN or CA conditions different ncRNAs are activated and affect different imprinted gene expression and thus leading to different clinical outcomes. Based on our findings, we will further perform in vitro functional analysis to elucidate the functions and mechanisms of these imprinted ncRNAs in AML tumorigenesis. Updated results of these analyzes will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

scholarly journals miR-3151 interplays with its host gene BAALC and independently affects outcome of patients with cytogenetically normal acute myeloid leukemia

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 249-258 ◽  
Author(s):  
Ann-Kathrin Eisfeld ◽  
Guido Marcucci ◽  
Kati Maharry ◽  
Sebastian Schwind ◽  
Michael D. Radmacher ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Myeloid Leukemia ◽  
Host Gene ◽  
High Expression ◽  
Expression Levels ◽  
Acute Myeloid

Abstract High BAALC expression levels are associated with poor outcome in cytogenetically normal acute myeloid leukemia (CN-AML) patients. Recently, miR-3151 was discovered in intron 1 of BAALC. To evaluate the prognostic significance of miR-3151 expression levels and to gain insight into the biologic and prognostic interplay between miR-3151 and its host, miR-3151 and BAALC expression were measured in pretreatment blood of 179 CN-AML patients. Gene-expression profiling and miRNA-expression profiling were performed using microarrays. High miR-3151 expression was associated with shorter disease-free and overall survival, whereas high BAALC expression predicted failure of complete remission and shorter overall survival. Patients exhibiting high expression of both miR-3151 and BAALC had worse outcome than patients expressing low levels of either gene or both genes. In gene-expression profiling, high miR-3151 expressers showed down-regulation of genes involved in transcriptional regulation, posttranslational modification, and cancer pathways. Two genes, FBXL20 and USP40, were validated as direct miR-3151 targets. The results of the present study show that high expression of miR-3151 is an independent prognosticator for poor outcome in CN-AML and affects different outcome end points than its host gene, BAALC. The combination of both markers identified a patient subset with the poorest outcome. This interplay between an intronic miR and its host may have important biologic implications.

scholarly journals Epigenetics Meets Genetics in Acute Myeloid Leukemia: Clinical Impact of a Novel Seven-Gene Score

2014 ◽  
Vol 32 (6) ◽  
pp. 548-556 ◽  
Author(s):  
Guido Marcucci ◽  
Pearlly Yan ◽  
Kati Maharry ◽  
David Frankhouser ◽  
Deedra Nicolet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
High Expression ◽  
Prognostic Impact ◽  
Sequencing Analysis ◽  
Gene Score ◽  
Expression Levels ◽  
Acute Myeloid

PurposeMolecular risk stratification of acute myeloid leukemia (AML) is largely based on genetic markers. However, epigenetic changes, including DNA methylation, deregulate gene expression and may also have prognostic impact. We evaluated the clinical relevance of integrating DNA methylation and genetic information in AML.MethodsNext-generation sequencing analysis of methylated DNA identified differentially methylated regions (DMRs) associated with prognostic mutations in older (≥ 60 years) cytogenetically normal (CN) patients with AML (n = 134). Genes with promoter DMRs and expression levels significantly associated with outcome were used to compute a prognostic gene expression weighted summary score that was tested and validated in four independent patient sets (n = 355).ResultsIn the training set, we identified seven genes (CD34, RHOC, SCRN1, F2RL1, FAM92A1, MIR155HG, and VWA8) with promoter DMRs and expression associated with overall survival (OS; P ≤ .001). Each gene had high DMR methylation and lower expression, which were associated with better outcome. A weighted summary expression score of the seven gene expression levels was computed. A low score was associated with a higher complete remission (CR) rate and longer disease-free survival and OS (P < .001 for all end points). This was validated in multivariable models and in two younger (< 60 years) and two older independent sets of patients with CN-AML. Considering the seven genes individually, the fewer the genes with high expression, the better the outcome. Younger and older patients with no genes or one gene with high expression had the best outcomes (CR rate, 94% and 87%, respectively; 3-year OS, 80% and 42%, respectively).ConclusionA seven-gene score encompassing epigenetic and genetic prognostic information identifies novel AML subsets that are meaningful for treatment guidance.

scholarly journals Pharmacogenomics to Predict Mucositis in Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2373-2373
Author(s):  
Jennifer Ahmed ◽  
Leila Becirevic ◽  
Natasha Emanuel ◽  
Molly E. Lofy ◽  
Hanh Tran ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Logistic Regression ◽  
Metabolic Pathway ◽  
Myeloid Leukemia ◽  
Regression Models ◽  
Interpatient Variability ◽  
Logistic Regression Models ◽  
Regulatory Motifs ◽  
Acute Myeloid

Abstract Introduction Acute myeloid leukemia (AML) is a heterogenous hematologic malignancy that primarily affects older adults, with a median age of diagnosis at 68 years and five-year relative survival of 29.5%. The incidence of AML diagnosis is expected to increase with an aging population in the United States, encouraging the exploration for treatment risk stratification to inform care. One factor impacting survivorship is treatment-related toxicity. Cytarabine (active metabolite, Ara-C) continues as a mainstay agent for initial induction regimens in AML, but efforts to minimize its toxicity remain a challenge. Interpatient variability presents another intricacy, where response to cytarabine can manifest as a subset of patients who have an inadequate response or those who are overly sensitive to its effects. Pharmacogenes in the cytarabine pathway may be responsible for this inconsistent response and could influence toxicity susceptibility. We conducted a retrospective analysis of AML patients treated with cytarabine to evaluate whether single nucleotide polymorphisms (SNPs) in its pharmacogenes are associated with treatment-related mucositis. Specifically, mucositis can negatively impact quality of life with pain and difficulty eating and swallowing, Thus, identifying patients likely to develop mucositis can assist in timely supportive care. Methods Patients from the University of Florida Shand's Hospital who received cytarabine during their first induction therapy from 2009 to 2019 for de novo AML were screened for mucositis within the first thirty days. We obtained FFPE tissues of these patients and extracted genomic DNA. Using TaqMan real-time PCR assays (QuantStudio 3) in-house, we genotyped for ten SNPs from genes involved in the cytarabine metabolic pathway. Logistic regression models were used to test for association between these SNPs and the incidence of mucositis. All analyses were performed using Rstudio v4.1.0. SNPs with significant results were then tested for other SNPs that occur in linkage disequilibrium (LD) using HaploReg v4.1, in addition to testing for association with gene expression using the Genotype-Tissue Expression Portal (GTEx). Results In total, 184 patients were included in this study, with 92 in each group - mucositis and no mucositis (control). The median age was 64 years, 58% were male, 83% were white, 12% African American or black, and 0.2% were Asian. No difference in the incidence of mucositis was observed by sex or race. Logistic regression models identified two SNPs significantly associated (p&lt;0.05) with incidence of mucositis within the first thirty days of cytarabine exposure. For rs5841, a synonymous coding SNP in NME4, presence of the variant T allele (CT/TT genotype) was associated with significantly increased incidence of mucositis (OR=1.51; 95% CI [1.09-2.11]) (Figure 1A and B). rs5841 occurs in LD with seven other SNPs impacting multiple regulatory motifs. Consistent with these results, presence of the T allele is associated with higher NME4 expression (Figure 1C), implying that higher ara-C activation in the variant T group is contributing to greater incidence of mucositis. For rs17103168, an intronic SNP in CMPK, patients homozygous for the variant allele (GG genotype) experienced significantly higher incidence of mucositis compared to those with AG or AA genotypes (OR=1.56; 95% CI [0.95-2.58]) (Figure 2A and B). This SNP occurs in LD with sixty other SNPs impacting numerous regulatory motifs as well. Presence of the GG genotype is associated with high gene expression (Figure 2C), suggesting that this increased gene expression in GG genotypes may result in higher ara-C levels, and subsequently increasing risk of toxicities. Conclusion Overall, we report a significant association between the risk of mucositis after initial cytarabine exposure and two SNPs in cytarabine metabolic pathway genes. Identifying those who may experience adverse toxicity using such SNP-based prediction models will allow for clinically meaningful interventions. Consideration of interpatient variability with cytarabine may lend valuable insight in shared-decision making between patient and clinician when weighing risks vs. benefit of treatment. Ongoing and future studies are focused on expanding this cohort to include evaluation of cytarabine pharmacogenomics with respect to disease progression and survival outcome in AML. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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