scholarly journals Study of HOTAIR LncRNA in AML patients in context to FLT3-ITD and NPM1 mutations status

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Mona Salah ◽  
Hamdy Zawam ◽  
Neven Bahaa Fouad ◽  
Nohair Soliman ◽  
Fatma Abdel Wahab Abdel Maksoud
Keyword(s):  
Gene Expression ◽  
Laboratory Data ◽  
Expression Level ◽  
Quantitative Detection ◽  
Npm1 Mutation ◽  
Free Survival ◽  
Regulatory Effects ◽  
Pre Treatment ◽  
Normal Controls ◽  
Gene Expression Levels

Abstract Background Long non-coding RNAs (LncRNAs) have recently been considered promising biomarkers for oncogenesis due to their epigenetic regulatory effects. HOTAIR is one of the oncogenic LncRNAs that was previously studied in different non-hematological malignancies. The current study set out to detect the expression level of HOTAIR LncRNA in AML patients concerning their clinical characteristics, laboratory data, FLT3-ITD, and NPM1 mutations, as well as treatment outcome. This study included quantitative detection of HOTAIR gene expression in 47 cases of AML using quantitative reverse transcription polymerase chain reaction, as well as NPM1 and FLT3-ITD genotyping. Results The HOTAIR expression was significantly higher in AML patients 6.87 (0.001) than in normal controls 1.66 (0.004–6.82) (p 0.007). The HOTAIR expression level was affected by chemotherapy, and it was correlated to hemoglobin level (p 0.001), age, total leukocytic count (p 0.022), and NPM1 mutation (p 0.017). HOTAIR gene expression level showed a correlation to relapse-free survival in the study group (p 0.04). Conclusion HOTAIR is overexpressed in patients with acute myeloid leukemia (AML). HOTAIR pre-treatment and post-chemotherapy gene expression levels can predict chemosensitivity and relapse.

Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3747-3754 ◽  
Author(s):  
Roel G. W. Verhaak ◽  
Chantal S. Goudswaard ◽  
Wim van Putten ◽  
Maarten A. Bijl ◽  
Mathijs A. Sanders ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Npm1 Mutation ◽  
Free Survival ◽  
Molecular Abnormalities ◽  
Cell Counts ◽  
Gene Expression Signatures ◽  
Acute Myeloid

Mutations in nucleophosmin NPM1 are the most frequent acquired molecular abnormalities in acute myeloid leukemia (AML). We determined the NPM1 mutation status in a clinically and molecularly well-characterized patient cohort of 275 patients with newly diagnosed AML by denaturing high-performance liquid chromatography (dHPLC). We show that NPM1 mutations are significantly underrepresented in patients younger than 35 years. NPM1 mutations positively correlate with AML with high white blood cell counts, normal karyotypes, and fms-like tyrosine kinase-3 gene (FLT3) internal tandem duplication (ITD) mutations. NPM1 mutations associate inversely with the occurrence of CCAAT/enhancer-binding protein-α (CEBPA) and NRAS mutations. With respect to gene expression profiling, we show that AML cases with an NPM1 mutation cluster in specific subtypes of AML with previously established gene expression signatures, are highly associated with a homeobox gene–specific expression signature, and can be predicted with high accuracy. We demonstrate that patients with intermediate cytogenetic risk AML without FLT3 ITD mutations but with NPM1 mutations have a significantly better overall survival (OS) and event-free survival (EFS) than those without NPM1 mutations. Finally, in multivariable analysis NPM1 mutations express independent favorable prognostic value with regard to OS, EFS, and disease-free survival (DFS).

ATF3 and EGR2 gene expression levels in sdLDL-treated macrophages of patients with coronary artery stenosis

2018 ◽  
Vol 42 (1-2) ◽  
pp. 23-29
Author(s):  
Sayed R. Hosseini-Fard ◽  
Mohsen Khosravi ◽  
Amaneh Yarnazari ◽  
Parisa Hassanpour ◽  
Abdollah Amirfarhangi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Coronary Artery ◽  
Cholesterol Metabolism ◽  
Quantitative Polymerase Chain Reaction ◽  
Fold Change ◽  
Expression Level ◽  
Control Group ◽  
Expression Levels ◽  
Vessel Disease ◽  
Gene Expression Levels

AbstractBackground:The metabolism of cholesteryl esters (CEs) is under the control of a gene network in macrophages. Several genes such asATF3andEGR2are related to cholesterol metabolism.Methods:In this study, theATF3andEGR2gene expression levels were evaluated in differentiated macrophages of subjects undergoing coronary artery angiography [controls (<5% stenosis), patients (>70% stenosis)] after treatment with small dense low density lipoprotein (sdLDL) particles. Monocytes were isolated using a RosetteSep Kit and were differentiated into macrophages using the M-CSF factor. A modified heparin-MgSO4-PEG method was used for the sdLDL preparation. TheATF3andEGR2gene expression levels were measured by the real-time quantitative polymerase chain reaction (RT-qPCR) technique.Results:In contrast with the control group (p=0.4), theATF3expression level reduced significantly in the differentiated macrophages from all patients [single vessel disease (SVD), fold change 17 times, p=0.02; two vessel disease (2VD), fold change 1.5 times, p=0.05; three vessel disease (3VD), fold change 3.5 times, p=0.04]. Also, theEGR2expression level reduced significantly in all groups (p<0.02). The gene fold changes had no significant differences between the patients (p>0.8).Conclusions:We propose that the failure ofATF3gene expression improves the CE synthesis after sdLDL influx. Furthermore, the reducedEGR2gene expression level in the sdLDL-treated groups may be a negative factor in cholesterol homeostasis.

scholarly journals In vivo measurements reveal a single 5’ intron is sufficient to increase protein expression level in C. elegans

2018 ◽  
Author(s):  
Matthew M. Crane ◽  
Bryan Sands ◽  
Christian Battaglia ◽  
Brock Johnson ◽  
Soo Yun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Expression Level ◽  
Protein Activity ◽  
Coding Sequence ◽  
Expression Levels ◽  
C Elegans ◽  
Hsp 90 ◽  
Gene Expression Levels

AbstractIntrons can increase gene expression levels using a variety of mechanisms collectively referred to as Intron Mediated Enhancement (IME). To date, the magnitude of IME has been quantified in human cell culture and plant models by comparing intronless reporter gene expression levels to those of intron-bearing reporter genes in vitro (mRNA, Western Blots, protein activity), using genome editing technologies that lacked full control of locus and copy number. Here, for the first time, we quantified IME in vivo, in terms of protein expression levels, using fluorescent reporter proteins expressed from a single, defined locus in Caenorhabditis elegans. To quantify the magnitude of IME, we developed a microfluidic chip-based workflow to mount and image individual animals, including software for operation and image processing. We used this workflow to systematically test the effects of position, number and sequence of introns on two different proteins, mCherry and mEGFP, driven by two different promoters, vit-2 and hsp-90. We found the three canonical synthetic introns commonly used in C. elegans transgenes increased mCherry protein concentration by approximately 50%. The naturally-occurring introns found in hsp-90 also increased mCherry expression level by about 50%. Furthermore, and consistent with prior results examining mRNA levels, protein activity or phenotypic rescue, we found that a single, natural or synthetic, 5’ intron was sufficient for the full IME effect while a 3’ intron was not. IME was also affected by protein coding sequence (50% for mCherry and 80% for mEGFP) but not strongly affected by promoter 46% for hsp-90 and 54% for the stronger vit-2. Our results show that IME of protein expression in C. elegans is affected by intron position and contextual coding sequence surrounding the introns, but not greatly by promoter strength. Our combined controlled transgenesis and microfluidic screening approach should facilitate screens for factors affecting IME and other intron-dependent processes.

scholarly journals Propranolol significantly reduced DNA polymerase β expression in patients with essential tremor

2021 ◽  
Vol 40 (3) ◽  
pp. 207-215
Author(s):  
Nefise Kandemir ◽  
Sercan Kenanoglu ◽  
Murat Gultekin ◽  
Nuriye Gokce ◽  
Hilal Akalin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Treatment Group ◽  
Dna Polymerase ◽  
Patient Group ◽  
Control Group ◽  
Expression Levels ◽  
Significant Difference ◽  
Propranolol Treatment ◽  
Pre Treatment ◽  
Gene Expression Levels

Background Essential tremor (ET) is the most common movement disorder. Propranolol is a first-line medication for ET. We aimed to evaluate the effect of propranolol on the expression of poly (ADP-ribose) polymerase 1 (PARP1) and DNA polymerase beta (POLB) genes, which are known to be related to neurodegenerative diseases, in patients with ET. MethodsThirty-five healthy volunteers and thirty-five patients followed up with essential tremors were included in a non-randomized control experimental study. Expressions of PARP1 and POLB genes were compared between the control group and the patient group. In addition, pre- and post-treatment gene expression levels and Fahn-Tolosa-Marin tremor scale values of the patient group were compared after 8 weeks of propranolol treatment. The Wilcoxon rank and Mann Whitney U tests were used to analyze the data. ResultsAt baseline, PARP1 expression was significantly lower in the ET group than in the control group. (p<0.001). POLB gene expression was significantly higher in the pre-treatment ET group than in the controls (p<0.05). There was no significant difference in PARP1 expression levels before and after 8 weeks of propranolol treatment. POLB gene expression was significantly higher in the pre-treatment group than in the post-treatment group (p<0.001). ConclusionPropranolol significantly decreased POLB gene expression but there was no significant difference in PARP1 gene expression levels in the patient group, after 8 weeks of propranolol treatment.

scholarly journals Estimating the proportion of disease heritability mediated by gene expression levels

2017 ◽  
Author(s):  
Luke J. O’Connor ◽  
Alexander Gusev ◽  
Xuanyao Liu ◽  
Po-Ru Loh ◽  
Hilary K. Finucane ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Disease Risk ◽  
Genetic Component ◽  
Effect Sizes ◽  
Expression Levels ◽  
Risk Variants ◽  
Regulatory Effects ◽  
Disease Effect ◽  
Gene Expression Levels

AbstractDisease risk variants identified by GWAS are predominantly noncoding, suggesting that gene regulation plays an important role. eQTL studies in unaffected individuals are often used to link disease-associated variants with the genes they regulate, relying on the hypothesis that noncoding regulatory effects are mediated by steady-state expression levels. To test this hypothesis, we developed a method to estimate the proportion of disease heritability mediated by the cis-genetic component of assayed gene expression levels. The method, gene expression co-score regression (GECS regression), relies on the idea that, for a gene whose expression level affects a phenotype, SNPs with similar effects on the expression of that gene will have similar phenotypic effects. In order to distinguish directional effects mediated by gene expression from non-directional pleiotropic or tagging effects, GECS regression operates on pairs of cis SNPs in linkage equilibrium, regressing pairwise products of disease effect sizes on products of cis-eQTL effect sizes. We verified that GECS regression produces robust estimates of mediated effects in simulations. We applied the method to eQTL data in 44 tissues from the GTEx consortium (average NeQTL = 158 samples) in conjunction with GWAS summary statistics for 30 diseases and complex traits (average NGWAS = 88K) with low pairwise genetic correlation, estimating the proportion of SNP-heritability mediated by the cis-genetic component of assayed gene expression in the union of the 44 tissues. The mean estimate was 0.21 (s.e. = 0.01) across 30 traits, with a significantly positive estimate (p < 0.001) for every trait. Thus, assayed gene expression in bulk tissues mediates a statistically significant but modest proportion of disease heritability, motivating the development of additional assays to capture regulatory effects and the use of our method to estimate how much disease heritability they mediate.

Molecular determinants of capecitabine efficacy in colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3606-3606
Author(s):  
D. Vallbohmer ◽  
H. Kuramochi ◽  
D. Shimizu ◽  
K. D. Danenberg ◽  
J. N. Nielsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Single Agent ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Expression Levels ◽  
Cox 2 ◽  
Gene Expression Levels

3606 Background: Capecitabine offers physicians a more convenient treatment for advanced colorectal cancer (CRC), with manageable toxicity and antitumor activity comparable to that of continuous-infusion therapies with 5-fluorouracil (5-FU). However, there are no validated and established predictive factors for clinical outcome of capecitabine efficacy in CRC. Therefore we investigated whether intratumoral mRNA expression levels of genes involved in the capecitabine/5-FU metabolism (cytidine deaminase (CDA), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), thymidine phosphorylase (TP), thymidylate synthase (TS)) and in angiogenesis (cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)) are associated with the clinical outcome of patients with metastatic CRC treated with first-line capecitabine. Methods: Thirty-seven patients with metastatic CRC were enrolled in this study and treated with single agent capecitabine.The intratumoral mRNA levels of CDA, COX-2, DPD, EGFR, FPGS; GGH, TP, TS, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture-microdissection methods and quantitative real-time PCR. Results: There were20 women and 17 men with a median age of 61 years (range 49–74). The median progression-free survival was 6.7 months (95% CI, 4.8–11.6 months), with a median follow up of 14.4 months (range: 1.3 to 18.7 months). Complete response was observed in 1 (3%), partial response in 6 (20%), stable disease in 14 (47%) and progressive disease in 9 (30%) patients (response was inevaluable in 7 patients). Higher gene expression levels of DPD were associated with resistance to capecitabine (P= 0.032; Kruskal-Wallis test). Patients with a lower mRNA amount of DPD (≤0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test). Conclusions: This pilot study suggests that intratumoral gene expression levels of DPD may be useful to predict the clinical outcome of patients with metastatic CRC with first-line single agent capecitabine treatment. Our data are hypothesis generating and should be validated in larger and prospective clinical trials. [Table: see text]

B7-H1 Molecules on Myeloma Cells Induce Aggressive Cell Behavior

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 474-474
Author(s):  
Hideto Tamura ◽  
Mariko Ishibashi ◽  
Taishi Yamashita ◽  
Asaka Kondo ◽  
Namiko Okuyama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Culture Supernatant ◽  
Plasma Cells ◽  
Proliferative Potential ◽  
Rt Pcr ◽  
Myeloma Cells ◽  
Expression Levels ◽  
Specific Ctls ◽  
Normal Controls ◽  
Gene Expression Levels

Abstract Abstract 474 Introduction: B7-H1 (CD274), a B7 family molecule, is expressed on antigen-presenting cells and plays crucial roles in T-cell regulation in various immune responses. We found that expression of B7-H1 molecules is also detected on some tumor cells and inhibits tumor-specific cytotoxic T lymphocytes (CTLs). Consistent with these data, it was reported that B7-H1 expression on tumor cells was associated with poor prognosis in some cancers, i.e., renal cell carcinoma, breast and ovarian cancer, etc. The expression levels of B7-H1 on plasma cells from multiple myeloma (MM) patients were reported to be higher than on those cells from patients with monoclonal gammopathy of undetermined significance (MGUS) and normal controls, suggesting that B7-H1 expression may be involved in the pathophysiology of MM. In the current study, we investigated the mechanism by which B7-H1 expression is induced on MM cells in the bone marrow (BM) microenvironment and analyzed characteristics of B7-H1+ MM cells in comparison with B7-H1– MM cells, i.e., proliferative potential, drug resistance, and sensitivity to myeloma-specific CTLs and whether B7-H1+ MM cells are associated with patients' disease status. Methods: We examined 14 human myeloma cell lines (HMCLs) and plasma cells from 40 MM patients, 10 MGUS patients, and 10 hematologically normal controls. B7-H1 expression levels were analyzed by flow cytometry (FCM) and real-time polymerase chain reaction (RT-PCR). Changes in B7-H1 expression levels on MM cells were analyzed after the cells were cultured in the presence of the human BM stromal cell line HS-5, its culture supernatant, various cytokines, or inhibitors of cytokines and transcription factors. Proliferative potential was compared between B7-H1+ and B7-H1– MM cells, including cell cycle status analyzed by propidium iodide (PI) staining, BrdU and Ki67 expression, and cell number in liquid culture. Finally, sensitivity to dexamethasone (DEX) and melphalan (MEL) and expression of apoptosis-related genes were compared between B7-H1+ and B7-H1– MM cells using FCM and RT-PCR, respectively. Results: 1) Although B7-H1 mRNA was detected in 9 of 14 HMCLs, only 3 cell lines expressed B7-H1 on their surface in FCM. B7-H1 expression on MM cells was significantly upregulated by co-culture with HS-5 cells or their culture supernatant. 2) Among cytokines present in the HS-5 cell supernatants, i.e., interleukin (IL)-6, IL-8, granulocyte-colony stimulating factor, and macrophage inflammatory protein 1 alpha, IL-6 alone induced B7-H1 expression on MM cells. Moreover, IL-6-neutralizing antibody dose dependently inhibited B7-H1 expression in the HS-5 cell culture supernatant. B7-H1 expression was downregulated by inhibiting STAT3, a transcription factor mediating IL-6 signaling. 3) The proliferative potential was higher in B7-H1+ cells in all assays. 4) Although KMS-27 myeloma cells lacking B7-H1 expression were killed by specific CTLs, KMS-27 cells that had B7-H1 expression induced on their surface resisted CTLs. 5) Nearly 20% of RPMI8226 cells expressed B7-H1, and DEX- and MEL-induced apoptosis was observed in the B7-H1– cell fraction alone. B7-H1 gene transfection in KMS-28PE cells conferred apoptosis resistance. Compared with B7-H1– RPMI8226 cells, B7-H1+ RPMI8226 cells showed higher gene expression levels of Bcl-2 and FasL and lower gene expression levels of caspase-8, caspase-9, and Fas. 6) Plasma cells from MM patients expressed significantly higher levels of B7-H1 than those cells from MGUS patients. One of 10 MM patients with International Scoring System (ISS) stage I, and 8 of 30 MM patients with ISS stage II/III were B7-H1 positive. Moreover, patients with CD45– myeloma, who were reported to have shorter survival, had higher expression levels of B7-H1 compared with CD45+ myeloma patients. In 4 of 8 MM patients, B7-H1 expression levels were upregulated in relapse or refractory status compared with levels at initial diagnosis. Conclusions: Our study indicated that IL-6 derived from BM stromal cells upregulates B7-H1 expression on myeloma cells, giving the cells gain more aggressive intrinsic proliferative potential and resistance to chemotherapeutic drugs and CTLs. The modulating B7-H1 pathway may have therapeutic potential in myeloma. Disclosures: No relevant conflicts of interest to declare.

Elevated Soluble IL-2Ra Levels Are Associated With Inferior Outcome and Is Independent Of MIPI Score in Patients With Mantle Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4256-4256
Author(s):  
Mohamad Bassam ◽  
Matthew J Maurer ◽  
Mary Stenson ◽  
Linda E Wellik ◽  
Christine Allmer ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
Cytokine Levels ◽  
Mantle Cell ◽  
Pre Treatment ◽  
Normal Controls

Abstract Blood cytokine elevations have been associated with non-Hodgkin's lymphoma (NHL) such as follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Although other types of NHL have been studied, to our knowledge, cytokine deregulation in mantle cell lymphoma (MCL) has not been comprehensively studied. In this study, we studied cytokine levels in untreated and relapsed MCL patients using a multiplex assay to determine the role of dysregulated cytokines in these patients and study any prognostic relevance that could be drawn from their effect on relapse and survival. Samples from two data sets of MCL patients were used for this study. The first dataset was pre-treatment serum samples from newly-diagnosed patients with MCL (n=88) from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource. The second dataset included pre-treatment plasma samples from relapsed MCL patients (n=20) treated on the MC0048G clinical trial studying the effect of everolimus in lymphoma patients. In addition, unrelated controls from a case-control study of lymphoma were included (n=15 serum, n=24 plasma). Thirty cytokines were assessed using a multiplex ELISA. Differences between cytokines in cases and controls were assessed using Wilcoxon rank-sum tests; associations between cytokines and event-free survival were assessed using Kaplan-Meier curves and Cox proportional hazards models. In the newly diagnosed MCL patients, IL-10 (p<0.0001), IL-1RA (p=0.001), IL-6 (p= 0.04), sIL-2Rα (p=0.005), and MIG (p=0.002) were elevated compared to normal controls. The only significantly elevated cytokine in the recurrent MCL cases compared to controls was sIL-2Rα (p= 0.0006). High levels (above median) of sIL-2Rα levels were associated with inferior event-free-survival (EFS) in both newly diagnosed (HR=2.61 (95% CI: 1.41-4.81, p= 0.0022) and relapsed MCL (HR=2.90, 95% CI: 1.08-7.80, p=0.035) patients; this remained significant after adjusting for MIPI (p=0.01 and 0.03, respectively). Moreover, in the relapsed MCL group eotaxin (p< 0.0001), IL-12 (p< 0.0001), and MCP-1 (p= 0.0002) were suppressed compared to normal controls. We hypothesized that STAT3 (pSTAT3) in MCL cells might be the possible cause behind IL-12 suppression. Indeed, 12/13 MCL samples from IL-12-suppressed relapsed MCL patients were pSTAT3+. When studying the association between cytokine levels and clinical characteristics in both untreated and relapsed MCL groups, sIL-2R was significantly associated with the MIPI score in both untreated (p<0.0001) and relapsed (p=0.007) MCL groups; and with performance status (p=0.005), lymphoma stage (p=0.004), and B symptoms (p=0.006) in the newly diagnosed MCL group.Figure 1Event-free survival of patients with untreated and relapsed MCL by sIL-2R levels.Figure 1. Event-free survival of patients with untreated and relapsed MCL by sIL-2R levels. Our study shows that cytokines are deregulated in both untreated and relapsed MCL patients. It emphasizes on the importance of sIL-2R in its association with negative clinical parameters and worse prognosis in MCL. These findings gives the rational for using sIL-2R along with MIPI and other parameters in predicting prognosis and further to monitor response in MCL. Furthermore, we showed that IL-12 is suppressed in relapsed MCL group and that pSTAT3 expression is a possible mechanism behind this suppression. Further studies are needed to investigate the effect of drugs that suppress pSTAT3 expression in IL-12 suppressed MCLs and disease progression in relapsed MCL patients. 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.

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