scholarly journals The LincRNA HOTAIRM1, Located in the HOXA genomic Region, impacts Prognosis in Acute Myeloid Leukemia and Is Associated with a Distinctive microRNA Signature

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1003-1003
Author(s):  
Marina Díaz-Beyá ◽  
Alfons Navarro ◽  
Salut Brunet ◽  
Josep F Nomdedeu ◽  
Anna Cordeiro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Hox Genes ◽  
Genomic Region ◽  
Expression Level ◽  
Molecular Characteristics ◽  
Npm1 Mutation ◽  
Acute Myeloid

Abstract Background: Non-coding RNAs (ncRNAs) have recently emerged as key regulators of diverse cellular processes, including leukemia. ncRNAs are classified according to their size as short (eg, microRNAs) or long ncRNAs. lincRNAs are long ncRNAs located in intergenic regions and have multiple regulatory functions, including gene expression regulation. Interestingly, active crosstalk between microRNAs and lincRNAs has been observed. lincRNAs are known to be deregulated in some cancers but their importance in acute myeloid leukemia (AML) is so far unknown. HOX genes play an important role in hematopoiesis and are deregulated in AML. lincRNAs are especially abundant in the clusters of HOX genes. HOTAIRM1, a myeloid lineage-specific lincRNA, is located at the 3’end of the HOXA cluster and seems to play a regulatory role in myelopoiesis. However, to date the potential prognostic role of HOTAIRM1 expression in AML has not been examined. Aims: To investigate first whether the expression of the lincRNA HOTAIRM1 is associated with the clinical, cytogenetic and molecular characteristics and microRNA expression in AML patients. Secondly, since intermediate risk (IR) AML patients have a highly diverse prognosis, we analyzed the potential prognostic value of HOTAIRM1 expression in IR-AML patients. Methods: To explore the expression level of HOTAIRM1 among different AML subtypes, we analyzed samples from 244 AML patients including CBF-rearranged AML (n=5), APL (n=4), MLL-rearranged AML (n=3), EVI1-rearranged AML (n=3), t(6;9) AML (n=9), AML with monosomal karyotype (n=3), and a large cohort of IR-AML (described below). For the analysis of prognostic value of HOTAIRM1, we analyzed specifically the outcome of 217 IR-AML patients (median age, 52; 51% males) sequentially included in CETLAM trials during the period 1995-2009. Molecular genotyping of this group identified NPM1 mutation (NPM1mut), FLT3-ITD, and biallelic CEBPA mutation (CEBPA mut) in 99 (45%), 79 (36%) and 17 (11%), respectively. The expression of HOTAIRM1 was analyzed using TaqMan® Gene Expression Assays (Applied Biosystems). microRNA and mRNA expression data were obtained in previous studies (Díaz-Beyá, Leukemia 2013). Statistical analyses were performed with BRB Array Tools, SPSS v20 and R v3.0. MaxStat package from R software was used to determine the optimal cutoff point of HOTAIRM1 expression. Results: Among all 244 patients, HOTAIRM1 expression was significantly different among the 7 included genetic subgroups (ANOVA p=0.0024), with the lowest levels observed in APL-AML patients and the highest in the t(6;9)AML patients. Within the IR-AML group, HOTAIRM1 overexpression was observed in NPM1mut patients (p<0.001). The prognostic study showed that high HOTAIRM1 expression was associated with shorter 5-year overall survival (OS) (27+11% vs.47+8%; p=0.009) shorter 5-year disease-free survival (LFS) (22+12% vs. 53+9%; p<0.001), and a higher cumulative incidence of relapse (CIR) at 5 years (55+15% vs. 34+8%; p=0.004). The effect on outcome was maintained within the subgroup with favorable molecular features (i.e., NPM1mut and CEBPAmut without FLT3-ITD) (OS: 75+11% vs. 39+29%; p=0.026). In the multivariate analysis including age, sex, WBC, NPM1mut, FLT3-ITD and number of treatment cycles for CR achievement as covariates, HOTAIRM1 expression emerged as an independent prognostic marker in OS (HR=2.44; 95% CI: 1.51-3.93; p<0.0001), LFS (HR=2.07; 95% CI: 1.31-3.24; p=0.002) and CIR (HR=2.05; 95% CI: 1.18-3.55; p=0.01). Supervised analysis by means of t-test based on multiple permutations revealed a distinctive 33-microRNA signature which correlated with HOTAIRM1 expression including miR-196b (p<0.001) located in the HOXA genomic region. Moreover, we correlated the expression of HOX genes and HOTAIRM1 and observed a positive correlation with HOXA4 gene expression (R2= 0.6; p=0.001). Conclusion: The expression level of the lincRNA HOTAIRM1 varied among different molecularly-defined AML. Interestingly, HOTAIRM1 expression level showed independent prognostic value within the IR-AML group. Moreover, HOTAIRM1 expression strongly correlates with its neighboring HOXA4 gene and harbors a distinctive microRNA signature. Our findings can pave the way for further studies of HOX-related lincRNAs and microRNAs regulatory networks and their influence on clinical outcome. Acknowledgments: ISCIII RH13/00205, SEHH, FIS13/00999 Disclosures No relevant conflicts of interest to declare.

scholarly journals H3K27me3 Level of the HIST1 Cluster Defines an Epigenetic Marker of Acute Myeloid Leukemia with Prognostic Value

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2326-2326
Author(s):  
Guillaume Tiberi ◽  
Aleksandra Pekowska ◽  
Claire Oudin ◽  
Adam Ivey ◽  
Thomas Prebet ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Molecular Characteristics ◽  
Significant Heterogeneity ◽  
Npm1 Mutation ◽  
Clinical Prognosis ◽  
H3k27me3 Level ◽  
The Impact ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults, characterized by significant heterogeneity in terms of biology and clinical outcome. Improvements in sequencing technologies have led to the discovery of frequent somatic mutations in epigenetic modifiers, placing epigenetic deregulation in the center of AML. Yet, the global view and the impact of this deregulation on disease characteristics are under investigation. To gain a more comprehensive understanding of epigenetic deregulation in AML, particularly the heterogeneous subset with normal karyotype (CN-AML), associated with intermediate clinical prognosis, we performed H3K27me3 profiling on CN-AML patient samples. Primary bone marrow or peripheral blood samples containing more than 80% of blasts were selected from the Institut Paoli-Calmettes Biological Resources Center inventory for the purpose of genetic and epigenetic studies. We initially analyzed 35 CN-AML samples by ChIP coupled with hybridization on oligonucleotide promoter arrays (Chip-chip) for genomic H3K27me3 distribution. Clustering analysis revealed 586 highly H3K27me3-variable genomic regions across patients corresponding to 461 genes mostly involved in chromatin organization. The heterogeneity in the H3K27me3 profile was characterized by a remarkable H3K27me3 enrichment at the chromosome 6 p22.2-22 region that encompasses 70 kbp within the major HIST1 cluster. This striking H3K27me3 enrichment was covering 11 histone genes and was partially overlapping with the focal deletion at 6p22 found in acute lymphoblastic leukemia. The HIST1 H3K27me3 enrichment profile clearly distinguished 2 groups of CN-AML patients based on their HIST1 H3K27me3 level. In order to independently extend this observation, we analyzed the H3K27me3 status by using ChIP followed by qPCR (ChIP-qPCR) at the same HIST1 genomic locations, in an independent cohort of 51 CN-AML patients. This revealed the presence of this abnormal epigenetic profile in about 50% of the patients. CN-AML samples were split in two groups, according to the median H3K27me3 enrichment levels at the HIST1 cluster genes. These two groups were analyzed for clinical and molecular characteristics. Patients with high HIST1 H3K27me3 level had a markedly higher incidence of NPM1 mutation (89% vs. 40%; p= 1.75x10-5) and a lower incidence of WT1 mutation (0% vs. 20%; p=0.028). No significant association was observed with FLT3 (ITD and TKD), IDH1/2, DNMT3A nor ASXL1 mutations. Patients with high HIST1 H3K27me3 level had a significant longer leukemia free survival at 5 years (allo-grafted patients censored, LFS-allo; 13.33 vs. 8.92 months p=0.0053). Moreover, multivariate analysis showed that HIST1 H3K27me3 status provided a more powerful prognostic indicator than the NPM1mut/FLT3-ITDneg and NPM1/FLT3-ITD genotypes. In conclusion,using epigenetic profiling, our analysis has enabled the discovery of a new epigenetic alteration that affects CN-AML and impacts prognosis. We demonstrate that the HIST1 cluster is targeted by epigenetic events that lead to high H3K27me3 level and predicts a good prognosis. This may help refine risk stratification in AML, identifying a further group of patients unlikely to benefit from allogeneic transplantation in first remission. Overall, our data provide a proof of concept that epigenetic profiling could be used to discover new biomarkers with prognostic value. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prognostic value of CIP2A gene expression in adult Egyptian acute myeloid leukemia patients

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Roxan E. Shafik ◽  
Azza M. Ibrahim ◽  
Fadwa Said ◽  
Naglaa M. Hassan ◽  
Hanan E. Shafik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Acute Myeloid

Long-Term Expansion and Self Renewal Is Contained in the CD34+, but Not the CD34- Subfraction of Nucleophosmin Mutated Acute Myeloid Leukemia Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1349-1349
Author(s):  
Carolien Woolthuis ◽  
Lina Han ◽  
Djoke van Gosliga ◽  
Philip Kluin ◽  
Edo Vellenga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hox Genes ◽  
Mutant Protein ◽  
Self Renewal ◽  
Cd34 Cells ◽  
Stromal Layer ◽  
Acute Myeloid

Abstract Mutations in the nucleophosmin (NPM) gene are found in about 30% of cases of acute myeloid leukemia (AML) and lead to a dislocation of the nucleophosmin protein from the nucleus to the cytoplasm (NPMc+ AML). NPMc+ AML shows distinctive biological and clinical features, including a unique gene expression profile, a distinct microRNA signature, low percentage of CD34+ cells, increased incidence of Flt3-ITD (about 40% of cases), good response to induction chemotherapy and (in the absence of Flt3-ITD) a favourable prognosis. Despite significant progress in the characterization of the NPMc+ AML subgroup, questions remain about the leukemia-initiating cell. Distinct features of NPMc+ AML, including multilineage involvement and overexpression of HOX-genes, may point to an early progenitor as the leukemia-initiating cell, but the characteristic low percentage of CD34+ cells may point to a more differentiated leukemic stem cell in NPMc+ AML. To gain more insight in the leukemia-initiating cell in AML with mutated NPM, NPMc+ AML cells were sorted based on the expression of CD34 (n=8, the percentage of CD34+ in the total AML fraction varied between 0.06 and 37%). Western blotting, using an antibody that specifically recognizes the nucleophosmin mutant protein revealed that the NPM mutant protein is expressed in both CD34+ and CD34− cells, proving that the CD34+ NPMc+ AML cells belong to the leukemic clone. This was verified by sequencing the NPM gene in CD34+ and CD34− AML cells. Importantly, culture of sorted CD34+ and CD34− NPMc+ AML cells on a stromal layer revealed that the CD34+ but not the CD34− cells of NPMc+ AML were capable of expanding and initiating long-term growth. In the first 5 weeks of culture an at least 16 fold (range 16–208) expansion of CD34+ AML cells was seen in 5 out of 6 NPMc+ AML cases. This expansion was associated with the formation of cobblestone areas (CAs) under the stromal layer within 3 weeks after plating. The NPMc+ AML cells which expanded in culture were able to expand further after replating in 4 out of 5 investigated cases (fold expansion range 1.6–2.5), indicative of the self renewal capacity of these CD34+ NPMc+ AML cells. Gene expression analysis of CD34+ and CD34− NPMc+ AML cells of 4 cases analyzed thus far revealed the presence of the characteristic HOX-overexpression profile in both CD34+ and CD34− NPMc+ AML cells. In summary, this study shows that the NPM mutation is not only present in CD34−, but also in CD34+ cells of NPMc+ AML and that the properties of long-term expansion and self renewal belong exclusively to the CD34+ subfraction of NPMc+ AML.

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).

scholarly journals The Expression of I-Mfa in Adult Patients with De Novo Acute Myeloid Leukemia and Its Clinical Significance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5316-5316
Author(s):  
Bing Xu ◽  
Huijuan Dong ◽  
Feili Chen ◽  
Yong Zhou ◽  
Jiabao Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Clinical Significance ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Adult Patients ◽  
Expression Level ◽  
Significant Difference ◽  
Median Expression ◽  
Acute Myeloid

Abstract Background: I-mfa has been identified as an inhibitor of MyoD and other related myogenic basic helix-loop-helix proteins. I-mfa contains a cysteine-rich C-terminal domain, and has been reported to function as transcriptional regulator of different pathways including Wnt signaling, c-jun N-terminal kinase signaling, and the regulatory properties of I-mfa depend on the C-terminal domain. Furthermore, recent studies have found that the I-mfa domain may have a close correlation with the development of myeloid neoplasms, however the role of I-mfa in adult patients with de novo acute myeloid leukemia still remain unclear. Aims: The aim of this study was to determine I-mfa expression in adult patients with de novo acute myeloid leukemia and its clinical significance. Methods: BM samples form 110 adult patients with de novo AML were analyzed. Of the 110 AML patients, 66 were males and 44 were females, with a mean age of 32 years( range from 12 to 77 years). Among them, 1 out of 110 patients was M1, 49 were M2, 14 were M4, 28 were M5, 1was M6 and 17 were acute unclassified leukemia. All patients received 1 to 2 cycles of induction of standard-dose cytarabine continuous infusion×7 days with idarubicin or daunorubicin×3days, fellowed by consolidation therapy with HiDAC and then stem cell transplantation according to patient’s condition. Real-time reverse transcription-polymerase chain reaction(RT-PCR) was used to detect the expression of I-mfa gene in 110 de novo adult AML patients, and the patients were divided into high and low I-mfa expression groups accordint to the median expression of I-mfa mRNA. Comparisons were performed using Mann-Whitney U test, Chi-square test and Kaplan-Meier method. Results:Distribution of I-mfa gene expression in different FAB subtypes was with no significant differences (P=0.169). The median age of AML pateints in low and high I-mfa gene epxression groups were 35 and 40 years old(P=0.162), and the median expression of I-mfa in 44 female patients and 66 male patients was 0.018 and 0.013 separately(P=0.728). What’s more, there was no significant difference of WBC, Hb level, PLT, bone marrow blast counts between the two groups (P＞0.05), and the I-mfa expression level was also not correlated with chromosome risk stratification and the expression of CD34 (P＞0.05). High I-mfa expression group had a lower complete remission rate than that in the low expression group (81.8% vs 63.6%, P=0.032), However, the overall survival rate was with no significant difference in the low and hign I-mfa gene expression groups(76.4% vs 76.4%, P=0.471). Conclusions: Our results showed high I-mfa expression correlates with a poor treatment response, the OS rate was with no significant difference in the two groups. There is somewhat correlation between the expression level of I-mfa gene and prognosis and the expression of I-mfa may be a prognostic factor for adult patients with de novo acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

Prognostic value of renin gene expression in acute myeloid leukemia

2018 ◽  
Vol 43 (2) ◽  
pp. 69
Author(s):  
NevinM.Al Azhary ◽  
NahelaA Shalaby ◽  
DeenaS Eissa ◽  
NaglaaM Hassan ◽  
AmanyA Saleh
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Renin Gene ◽  
Acute Myeloid

Molecular Markers Predicting Clinical Outcome in Patients with Intermediate-Risk Acute Myeloid Leukemia Receiving Autologous Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 604-604
Author(s):  
Jordi Esteve ◽  
Susana Kalko ◽  
Montserrat Torrebadell ◽  
Mireia Camos ◽  
Pedro Jares ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Intermediate Risk ◽  
Npm1 Mutation ◽  
Acute Myeloid

Abstract Post-remission therapy in patients with acute myeloid leukemia (AML) is assigned according to the predictable biological risk of the disease, mainly based on cytogenetics. Nonetheless, optimal post-remission strategy for the intermediate-risk subtype, given the prognostic heterogeneity of this category, is currently undefined. Analysis of potentially relevant molecular features within this subgroup might contribute to clarify the role of autologous stem cell transplantation (autoHSCT) in these patients. Thirty seven patients (age: 53, 15–66; 51% female) diagnosed with intermediate-risk de novo AML during the period 1994–2006 who received an autoHSCT in first complete response were included in the study. Pre-transplant therapy was similar in all patients, consisting of standard induction chemotherapy (ICE, n=8, IDICE, n=29) and one cycle of high-dose ara-C-based consolidation chemotherapy. Internal tandem duplication of flt-3 (flt-3 ITD) and exon 12 NPM1 mutations were studied by either PCR or RT-PCR following standard methods. Gene expression profiling was examined in 28 patients with oligonucleotide HGU133 Plus 2.0 arrays (Affymetrix). Gene expression measures were normalized using RMA methodology (Affy package), and dChip v1.3 and Limma software (Bioconductor) were used for unsupervised and supervised analyses. In order to identify genes with prognostic value, a supervised analysis based on patients’ outcome (relapsed patients vs. long-term responders, i.e. >2-year duration) was performed. The combined results of NPM mutation and flt-3 ITD defined three subgroups of patients with different outcome: group 1 (n=12), constituted by patients with mutated NPM1 without flt-3 ITD; group 2 (n=20), which included patients with neither NPM1 mutation or flt-3 ITD; and group 3 (n=5), defined by flt-3 ITD regardless NPM1 mutational status. Thus, 5-year survival of these 3 subgroups of patients was 91%±9%, 52%±12%, and 20%±18%, respectively (p=0.02; see figure). Preliminary results of multiple gene profile comparisons between subgroups of patients with different outcome disclosed a cluster of genes with differential expression. Thus, in the most significant balanced comparison, 1238 genes were found to vary significantly in the unsupervised analysis, and 109 differentially expressed genes were identified in the supervised analysis. Interestingly, overexpression of genes such as TNF, RETN, CFLAR, SLC16A7, ENG, CD48, PLCR1, and SULTB1 correlated with a high relapse risk, whereas increased expression of YY1, FBXL12 and EXOSC6 were associated with a favorable outcome. In conclusion, presence of NPM1 mutation and flt-3 ITD are strong predictors of the outcome after autoHSCT in patients with intermediate-risk AML. Furthermore, genome-wide analysis may contribute to further define gene clusters with prognostic significance in patients with cytogenetically intermediate-risk AML receiving autoHSCT as consolidation therapy. Figure Figure

The Relationship between Mutation in HOXB1 Gene and Acute Myeloid Leukemia

2019 ◽  
Author(s):  
Mohammad Yahya Vahidi Mehrjardi ◽  
Seyed Mohsen Aghaei Zarch ◽  
Mohammadreza Dehghani
Keyword(s):  
Gene Expression ◽  
Experimental Study ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Rna Extraction ◽  
Expression Level ◽  
Wild Type ◽  
Significant Difference ◽  
Heterozygous Carriers ◽  
Acute Myeloid

Background: HOX genes are an exceedingly preserved family of homeodomain-involving transcription factors. They are related to a number of malignancies, comprising acute myeloid leukemia (AML). This study aimed to evaluate the effect of HOXB1 7bp deletion mutation on HOXB1gene expression in 36 individuals. Materials and Methods: The present cross-sectional study was done on a large Iranian family. In this experimental study, 5 homozygous 7bp deletion individuals along with their unaffected siblings and their parents were investigated. The candidate gene, HOXB1 was screened and analyzed in blood samples of these participants. After RNA extraction, cDNA was synthesized according to manufacturer’s protocol. HOXB1 expression level was analyzed by 2ΔΔCT method. All laboratory procedures used in this experimental study were carried out in genetic laboratory of Shahid Sadoughi University of Medical Sciences. Results: Sequence analysis of HOXB1 gene by ABI Prism 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA) revealed a family with 5 homozygous (22±17 years) and 22 healthy heterozygous carriers (42±19 years) for 7bp deletion in HOXB1 gene along with 9  healthy wild type (55±41 years). Gene expression analysis by RT-qPCR demonstrated that expression level of HOXB1 gene in wild type and heterozygous carriers specimens had similar levels (p=0.05). Conclusion: Although HOXB1 mutations has been reported in AML, but association between HOXB1 mutation and AML was not found in our study. Additionally, HOXB1 expression levels showed no significant difference between wild type and heterozygous carriers. So, HOXB1 gene expression cannot provide a powerful tool to differentiate wild type from heterozygous carries.

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.

Sign in / Sign up

Export Citation Format

Share Document