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.

Altered Regulation of Imprinted Non-Coding RNA Genes in Acute Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3456-3456 ◽  
Author(s):  
Ming-Yu Yang ◽  
Jan-Gowth Chang ◽  
Pai-Mei Lin ◽  
Jui-Feng Hsu ◽  
Cheng-Han Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Large Scale ◽  
Conflicts Of Interest ◽  
Imprinted Genes ◽  
Healthy Individuals ◽  
Regulatory Functions ◽  
Acute Myeloid

Abstract Abstract 3456 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. Imprinted genes tend to occur in clusters and ncRNAs have been found at all well-characterized imprinted clusters. 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, a panel of 24 human imprinted ncRNAs genes, including ampd3, cpa4, snuf, rasgrf1, slc22a3, lgf2, treb3c, gabrb3, c15orf2, sfmbt2, rtl1, copg2, h19, l3mbtl, ppp1r9a, tspan32, lnpp5f, impact, nr3251, nr3252, znf215, prim2, peg3as and znf264, has been mined using Bioinformatics approach. We investigated the expression of these imprinted ncRNA genes using real-time quantitative RT-PCR in 67 newly-diagnosed acute myeloid leukemia patients with normal karyotypes (AML-NK), 22 AML patients with abnormal karyotypes (AML-AK), and 39 healthy individuals. In AML-NK patients, the expression of lgf2, h19, slc22a3, copg2, and impact were significantly upregulated than in healthy individuals (p < 0.0001). In AML-AK patients, besides lgf2, h19 and impact genes, ampd3 and gabrb3 were also significantly upregulated than in healthy individuals (p < 0.0001). Expression of igf2 was almost undetectable in healthy individuals but drastically increased in all AML patients. Both lgf2 and h19 were significantly increased in both AML-NK and AML-AK patients. From our preliminary results, it is reasonable to hypothesize that loss imprinting of lgf2/h19 is critical for the leukemogenesis of AML and under NK or AK conditions different additional ncRNAs are activated and affect different imprinted gene expression and thus leading to different clinical outcomes. Based on our findings, we will further perform methylation analysis of promoter CpG sites in AML patients to investigate if hypomethylation is responsible for the upregulation of these imprinted ncRNAs. We will also carry out in vitro functional analysis to elucidate the functions and mechanisms of these imprinted ncRNAs in AML tumorigenesis. Updated results of these analysis will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Gene Expression Patterns Associated with Cytarabine Pharmacology and Outcome in Pediatric Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 114-114
Author(s):  
Jatinder K. Lamba ◽  
Kristine Crews ◽  
Stanley Pounds ◽  
Xueyuan Cao ◽  
Varsha Gandhi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Dna Synthesis ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Expression Patterns ◽  
Leukemic Cells ◽  
Leukocyte Counts ◽  
Risk Of Relapse ◽  
Acute Myeloid

Abstract Abstract 114 To identify genes that influence responses to cytarabine (ara-C) treatment, we explored the association of gene expression in leukemic cells at diagnosis with multiple pharmacological and clinical end-points in children with acute myeloid leukemia (AML) treated with ara-C on the St. Jude AML97 clinical trial. We applied a novel statistical procedure, PRojection Onto the Most Interesting Statistical Evidence (PROMISE; PR), to identify genes with expression levels associated with clinical and pharmacological endpoints. To do this, we first defined the following values of the clinical and pharmacological variables as “therapeutically beneficial” :higher leukemic cell ara-C triphosphate levels, lower DNA synthesis values on days 1 and 2 of treatment relative to baseline, decreases in leukocyte counts on day 2 of treatment, improved response and decreased risk of relapse, death, or second malignancy. We considered a gene to show a therapeutically beneficial pattern of association if its expression was positively correlated with ara-CTP levels, negatively correlated with DNA synthesis levels, negatively correlated with decrease in leukocyte counts on day 2, positively correlated with better treatment response, and negativelycorrelated with the risk of relapse or death. A gene showed a therapeutically detrimental pattern of association if its expression had the opposite correlations with the clinical and pharmacological variables. We performed five variable (PR5 using early pharmacologically interesting phenotype measures) or seven variable (PR7 all the above indicated phenotypes) PROMISE analyses. PR5 identified 275 beneficial probe sets and 69 detrimental probe sets (p ≤ 0.005). PR7 analysis identified 112 beneficial probe sets and 115 detrimental probe sets (p ≤ 0.005). To confirm these results, we performed a PROMISE for a cohort of patients treated with ara-C and other agents on the AML02 protocol. Gene expression in leukemic cells at diagnosis was analyzed for a beneficial or detrimental pattern of association with three phenotypes (PR-3); diagnostic blast ara-C cytotoxicity, minimal residual disease (MRD) and event-free survival (EFS). Eighty-one probe sets identified by PR5 or PR7 analyses in the initial cohort were confirmed in the PR-3 analysis of AML02 data. Genes identified in the present study may serve as predictive markers of response and candidates for future drug development. Disclosures: No relevant conflicts of interest to declare.

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.

scholarly journals Granulocyte Colony-Stimulating Factor Inhibits CXCR4/SDF-1 Signaling and Overcomes Stromal-Mediated Drug Resistance in Acute Myeloid Leukemia Via Mir-146a

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4763-4763 ◽  
Author(s):  
Hua Zhong ◽  
Lan Xu ◽  
Xin Li ◽  
Xian-fu Sheng ◽  
Fang-yuan Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Western Blotting ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Leukemia Cells ◽  
Hl60 Cells ◽  
Expression Levels ◽  
Qrt Pcr ◽  
Smad4 Expression ◽  
Acute Myeloid

Abstract CAG regimen was widely used in the clinical treatment of acute myeloid leukemia (AML). However, the mechanisms of G-CSF in the CAG regimen remain unknown. For the purpose of better elucidating the function of G-CSF, we evidenced that G-CSF could enhance HL60 and primary leukemia cells proliferation in vitro. Meanwhile, transwell migration experiments demonstrated that G-CSF, similar as the CXCR4 antagonist AMD3100, could remarkably inhibit the chemotaxis of HL60 cells induced by the chemokines released from marrow stromal cells (Fig 1). qRT-PCR and Western blotting results showed that the expression of miR-146a was up-regulated after G-CSF treatment, while the expression levels of CXCR4 and smad4 were down-regulated (Fig 2). CXCR4 and Smad4 expression levels in miR-146a over expression lentivirus infected HL60 cells were significantly decreased, which manifested the direct or indirect targeted relationship between miR-146a and CXCR4/Smad4. Our qRT-PCR and Western blotting results also showed an involvement of NF-KB in G-CSF induced up-regulation of miR-146a in AML cells. G-CSF activated NF-KB in the cells. Activated NF-KB induced the up-regulation of miR-146a expression. Sanguinarine, an inhibitor of NF-KB significantly inhibited miR-146a expression. We further demonstrated the involvement of NF-KB in the regulation of G-CSF in CXCR4 and Smad4 expression (Fig 3). Our study demonstrated that G-CSF not only could induce resting leukemia cells into proliferation cell cycle, but also could inhibit chemotaxis of leukemia cells. We elucidated the mechanism of G-CSF/NF-KB/miR-146a/CXCR4 signaling pathway in CAG treatment of AML. The expression levels of MiR-146a /CXCR4 /Smad4 may be selected as the clinical markers for CAG protocol choosing. Disclosures No relevant conflicts of interest to declare.

scholarly journals Importance of Altered Gene Expression of Metalloproteinases 2, 9, and 16 in Acute Myeloid Leukemia: Preliminary Study

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Jacek Pietrzak ◽  
Marek Mirowski ◽  
Rafał Świechowski ◽  
Damian Wodziński ◽  
Agnieszka Wosiak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Proteolytic Enzymes ◽  
Regulation Of Gene Expression ◽  
Expression Level ◽  
Altered Expression ◽  
Cytogenetic Changes ◽  
The Impact ◽  
Acute Myeloid

Acute myeloid leukemia is a group of hematological neoplasms characterized by a heterogeneous course and high mortality. The important factor in the neoplastic process is metalloproteinases, proteolytic enzymes capable of degrading various components of the extracellular matrix, which take an active part in modifying the functioning of the cell, including transformation to cancer cell. They interact with numerous signaling pathways responsible for the process of cell growth, proliferation, or apoptosis. In the present study, changes in the expression of MMP2, MMP9, and MMP16 genes between patients with AML and people without cancer were examined. The impact of cytogenetic changes in neoplastic cells on the expression level of MMP2, MMP9, and MMP16 was also assessed, as well as the impact of the altered expression on the effectiveness of the first cycle of remission-inducing therapy. To evaluate the expression of all studied genes MMP2, MMP9, and MMP16, SYBR Green-based real-time PCR method was used; the reference gene was GAPDH. For two investigated genes MMP2 and MMP16, the lower expression level was observed in patients with AML when compared to healthy people. The MMP9 gene expression level did not differ between patients with AML and healthy individuals which may indicate a different regulation of gene expression in acute myeloid leukemia. However, no correlation was observed between the genes’ expression of all tested metalloproteinases and the result of cytoreductive treatment or the presence of cytogenetic changes. The obtained results show that the expression of MMP2 and MMP16 genes is reduced while the expression of MMP9 is unchanged in patients with acute myeloid leukemia. This may indicate a different regulation of the expression of these genes, and possible disruptions in gene transcription or posttranscriptional mechanisms in the MMP2 and MMP16 genes, however, do not affect the level of MMP9 expression. Obtained results in AML patients are in contrary to various types of solid tumors where increased expression is usually observed.

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.

scholarly journals Effect of Metabolic Reprogramming on the Biological Activity of Acute Myeloid Leukemia Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5227-5227
Author(s):  
Tongyuan Liu ◽  
Dengju Li ◽  
Jianfeng Zhou
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Biological Activity ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chemotherapeutic Agents ◽  
Metabolic Reprogramming ◽  
Gene Microarray ◽  
Acute Myeloid

Abstract ABSTRACT Metabolic reprogramming of acute myeloid leukemia (AML) cell lines has been described as a compensatory adaptation to fulfill their energy requirements for its rapid proliferation. In this study,we examined the role of the glutamine (Gln) removal or inhibition of glutaminase by GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol- 2-yl) ethyl sulfide(BPTES) in AML cell lines SKM-1 to Observe whether it has an effect on the biological activity of SKM-1 cells. Our results indicated that inhibit glutamine uptake or utilization can inhibit cell growth and induce apoptosis in AML. we used Long non-coding RNAs (LncRNAs) Gene Microarray to analyze gene expression after Gln deprivation treatment. We found that the expression of MT2A, MT1X, MT3, MT1H, MT1F and MT1E in the metallothionein (MT) gene family was significantly upregulated and the expression of AGT、CSF1R、PAK7、MYCN、ARG1 was significantly downregulated . We further analysed the expression of MT isogenes by quantitative real-time PCR (RT-PCR). The results showed that the gene expression of the MT gene family was upregulated, consistent with the results of the Gene Microarray. These findings indicate that metallothionein may play an important role in the glutamine metabolic pathway of AML cells. metformin, a commonly used antidiabetic drug, play an important role in Glucose Metabolism.We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in SKM-1 cell lines and its anti-leukemic activity was enhanced when used in combination with Gln deprivation or Cytarabine. These findings show that Gln deprivation or Metformin enhance the sensitivity of SKM-1 cell line to chemotherapeutic agents. Taken together , targeting amino acid metabolism and glucose metabolism are promising new therapeutic strategies to enhance the efficacy of chemotherapeutic agents in AML. Conflict of interest No relevant conflicts of interest to declare. Acknowledgments: Tongyuan Liu analyzed the data, plotted the tables and figures and wrote the paper; Dengju Li designed projects and revised the paper. This work was supported by the National Natural Science Foundation of China (Grant no. 81770168). Disclosures No relevant conflicts of interest to declare.

Association Between Genetic Polymorphism in DNA Repair Genes and Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4131-4131
Author(s):  
Hee Nam Kim ◽  
Nan young Kim ◽  
Li Yu ◽  
Huong Thi Thanh Tran ◽  
Yeo-Kyeoung Kim ◽  
...  
Keyword(s):  
Dna Repair ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Large Scale ◽  
Conflicts Of Interest ◽  
Cancer Susceptibility ◽  
Dna Repair Genes ◽  
Repair Capacity ◽  
Repair Genes ◽  
Acute Myeloid

Abstract Abstract 4131 Genetic variants in DNA repair genes may affect DNA repair capacity and modulate cancer susceptibility. We analyzed genetic polymorphisms of 11 DNA repair genes: XRCC4, BRCA1, WRN, RAD51, XRCC3, ERCC1, ERCC2, XPC, OGG1, XRCC1 and MGMT to evaluate the association and risk of acute myeloid leukemia (AML). A large-scale population-based, case-control study of 1700 controls and 659 cases was conducted in Chonnam National University Hwasun Hospital, Korea. Three single-nucleotide polymorphisms(SNPs), ERCC1 IVS5 +33 CC, WRN 787 GG and XRCC1 399 GA genotypes were associated with decreased risk for AML [odds ratio (OR) = 0.71; 95% confidence interval (CI) = 0.54-0.92, p=0.01 for IVS5 +33 CC, 0.67; 0.50–0.89, p=0.006 for 3149 GG and 0.81; 0.67–0.98, p=0.031 for 1316 GA]. We found no differences in the XRCC4 S307, BRCA1 P87L, RAD51 –G135C, XRCC3 T241M, ERCC2 K751Q, XPC K939Q, OGG1 S326C and MGMT L84F genotypes. Our results suggest that these 3 SNPs in DNA repair genes may affect AML susceptibility by modulating activities to maintain the genome integrity of each individual. Disclosures: No relevant conflicts of interest to declare.

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