Identification of Distinct inv(16) Subclasses in Adult Acute Myeloid Leukemia Based on Gene Expression Profiling.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2037-2037
Author(s):  
Lars Bullinger ◽  
Claudia Scholl ◽  
Eric Bair ◽  
Konstanze Dohner ◽  
Stefan Frohling ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Expression Patterns ◽  
Rank Test ◽  
Survival Times ◽  
Strong Trend ◽  
Candidate Target ◽  
Acute Myeloid

Abstract Recurrent cytogenetic aberrations have been shown to constitute markers of diagnostic and prognostic value in acute myeloid leukemia (AML). However, even within the well-defined cytogenetic AML subgroup with an inv(16) we see substantial biological and clinical heterogeneity which is not fully reflected by the current classification system. To better characterize this cytogenetic group on the molecular level we profiled gene expression in a series of adult AML patients (n=26) with inv(16) using 42k cDNA microarrays. By unsupervised hierarchical clustering we observed that samples with inv(16) separated primarily into two different subgroups. These showed no significant differences regarding known risk factors like age, WBC, LDH, etc. However, these newly defined inv(16)-subgroups were characterized by distinct clinical behavior. There was a strong trend towards unfavorable outcome with shorter overall survival times in one group (P=0.09, log rank test). Since the primary translocation/inversion events themselves are not sufficient for leukemogenesis, distinct patterns of gene expression found within each of these cytogenetic groups may suggest alternative cooperating mutations and deregulated pathways leading to transformation. Therefore, we performed a supervised analysis to determine the characteristic gene expression patterns underlying the cluster-defined subgroups. This Significance Analysis of Microarrays (SAM) method identified 260 genes significantly differentially expressed between the two newly defined inv(16)-subgroups (false discovery rate = 0.002). High expression levels of JUN, JUNB, JUND, FOS and FOSB characterized the first inv(16) subgroup (having less favorable prognosis). FOS gene family members can dimerize with proteins of the JUN family, forming the transcription factor complex AP-1 which has been implicated in the regulation of cell proliferation, differentiation, and transformation. Among the second subgroup, the proto-oncogene ETS1,displayed elevated expression, possibly resulting from aberrant MEK/ERK pathway activation as these cases also showed an over-expression of MAP3K1 and MAP3K2. In conclusion, both supervised and unsupervised methods provide numerous insights into the pathogenesis of AML with inv(16), identifying clinically significant patterns of gene expression, as well as candidate target genes involved in leukemogenesis.

Gene Expression Profiling Identifies Distinct Subclasses in Core Binding Factor Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 673-673
Author(s):  
Lars Bullinger ◽  
Stephan Kurz ◽  
Konstanze Dohner ◽  
Claudia Scholl ◽  
Stefan Frohling ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Patterns ◽  
The Other ◽  
Rank Test ◽  
Core Binding Factor ◽  
Log Rank Test ◽  
Binding Factor ◽  
Acute Myeloid

Abstract Recurrent cytogenetic aberrations have been shown to constitute markers of diagnostic and prognostic value in acute myeloid leukemia (AML). However, even within well-defined cytogenetic AML subgroups with an inv(16) or a t(8;21) we see substantial biological and clinical heterogeneity which is not fully reflected by the current classification system. Therefore, we profiled gene expression in a large series of adult AML patients with core binding factor (CBF) leukemia [inv(16) n=55, t(8;21) n=38] using a whole genome DNA microarray platform in order to better characterize this disease on the molecular level. By unsupervised hierarchical clustering based on 8556 filtered genes we observed that our CBF leukemia samples separated primarily into three different subgroups. While two of the subgroups were characterized by inv(16) and t(8;21) cases, respectively, the third subgroup contained a mixture of both cytogenetic groups. There was no obvious correlation with known secondary aberrations or molecular marker like FLT3-ITD, NRAS and KIT mutations between the cases in the mixed subgroup and the others. However, the newly defined inv(16)/t(8;21)-subgroup (n=35) was characterized by distinct clinical behavior with shorter overall survival times (P=0.029; log rank test) compared to the other two groups. Unsupervised analyses within the inv(16) and t(8;21) cases also revealed corresponding inv(16) and t(8;21) subgroups with a strong trend towards inferior outcome (P=0.11 and P=0.09, respectively; log rank test). Since the primary translocation/inversion events themselves are not sufficient for leukemogenesis, distinct patterns of gene expression found within each of these cytogenetic groups may suggest alternative cooperating mutations and deregulated pathways leading to transformation. Therefore, we performed a supervised analysis to determine the characteristic gene expression patterns underlying the cluster-defined subgroups. We identified 528 genes significantly differentially expressed between the newly defined inv(16)/t(8;21)-subgroup and the other CBF cases (significance analysis of microarrays, false discovery rate < 0.001). Potential candidates for cooperating pathways characterizing the mixed inv(16)/t(8;21)-subgroup included e.g. AVO3, a member of the mTOR pathway, oncogene homologs like LYN and BRAF, as well as FOXO1A and IL6ST which have been previously identified to correlate with outcome in AML (Bullinger et al., N Engl J Med350:1605, 2004). In conclusion, while the observed signatures remain to be validated for their functional relevance, both supervised and unsupervised methods provide numerous insights into the pathogenesis of CBF AML, identifying clinically significant patterns of gene expression, as well as candidate target genes involved in leukemogenesis.

scholarly journals Predicting Complete Remission of Acute Myeloid Leukemia: Machine Learning Applied to Gene Expression

2019 ◽  
Vol 18 ◽  
pp. 117693511983554 ◽  
Author(s):  
Ophir Gal ◽  
Noam Auslander ◽  
Yu Fan ◽  
Daoud Meerzaman
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Statistical Significance ◽  
Expression Patterns ◽  
Pathway Enrichment Analysis ◽  
Data Set ◽  
Acute Myeloid

Machine learning (ML) is a useful tool for advancing our understanding of the patterns and significance of biomedical data. Given the growing trend on the application of ML techniques in precision medicine, here we present an ML technique which predicts the likelihood of complete remission (CR) in patients diagnosed with acute myeloid leukemia (AML). In this study, we explored the question of whether ML algorithms designed to analyze gene-expression patterns obtained through RNA sequencing (RNA-seq) can be used to accurately predict the likelihood of CR in pediatric AML patients who have received induction therapy. We employed tests of statistical significance to determine which genes were differentially expressed in the samples derived from patients who achieved CR after 2 courses of treatment and the samples taken from patients who did not benefit. We tuned classifier hyperparameters to optimize performance and used multiple methods to guide our feature selection as well as our assessment of algorithm performance. To identify the model which performed best within the context of this study, we plotted receiver operating characteristic (ROC) curves. Using the top 75 genes from the k-nearest neighbors algorithm (K-NN) model ( K = 27) yielded the best area-under-the-curve (AUC) score that we obtained: 0.84. When we finally tested the previously unseen test data set, the top 50 genes yielded the best AUC = 0.81. Pathway enrichment analysis for these 50 genes showed that the guanosine diphosphate fucose (GDP-fucose) biosynthesis pathway is the most significant with an adjusted P value = .0092, which may suggest the vital role of N-glycosylation in AML.

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.

scholarly journals KDM7A Is Targeted By MiR-155 in Acute Myeloid Leukemia and Impacts Differentiation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3641-3641 ◽  
Author(s):  
Maya D. Hughes ◽  
Valerie A. Morris ◽  
Carrie Cummings ◽  
Soheil Meshinchi ◽  
Vivian G. Oehler
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Cell Differentiation ◽  
Binding Sites ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous disease that develops secondary to the acquisition of mutations that disrupt cell differentiation, proliferation and survival. MicroRNAs (miRNAs or miRs) are short non-coding RNA molecules that modulate post-transcriptional gene expression by either cleaving or repressing translation of target mRNA transcripts. Differential expression of miRNAs has been identified in AML and noted to correlate with specific disease characteristics, cytogenetic abnormalities and prognosis. MiR-155 expression is upregulated in both adult and pediatric patients with cytogenetically normal AML (CN-AML) and correlates with adverse clinical outcomes. Specifically, we have shown that high miR-155 expression is associated with an increased incidence of induction chemotherapy failure and inferior overall and event free survival. However, how miR-155 up-regulation contributes mechanistically to adverse clinical outcomes is poorly understood. In prior work, we correlated the expression of predicted or validated miR-155 target genes with miR-155 expression in a gene expression profiling (GEP) dataset of pediatric AML samples. We identified 22 candidates with inversely correlated expression by GEP for further validation in diagnostic bone marrow specimens from children with the highest miR-155 expression levels (n=9) vs. children with the lowest miR-155 expression levels (n=9). Although the expression of miR-155 inversely correlated with 9 target genes, only expression of the putative target KDM7A demonstrated a statistically significant difference in expression between low and high miR-155 expressing cases (p = 0.03). KDM7A is a lysine-specific histone demethylase enzyme that may play a role in regulating differentiation by impacting transcriptional elongation. Computational software programs, i.e. TargetScan, identified two predicted miR-155 binding sites in the KDM7A 3'UTR. To evaluate whether miR-155 directly binds to the KDM7A 3'UTR, we cloned two regions of the KDM7A 3'UTR containing predicted miR-155 binding sequences into luciferase reporter vectors and then mutated the binding sites by site-directed DNA mutagenesis. We validated that both predicted binding sites in KDM7A 3'UTR were direct miR-155 targets using HEK293T cells. Next, we examined the impact of miR-155 overexpression in K562 cells, an acute leukemia cell line that express very low levels of endogenous miR-155, and can be differentiated along the erythroid lineage after hemin exposure. KDM7A RNA expression was decreased 16-fold in miR-155 versus control lentivirally transduced K562 cells as detected by qPCR. KDM7A protein expression was also decreased in miR-155 versus control expressing K562 cells as measured via Western blot. These data demonstrate that KDM7A is a previously uncharacterized target of miR-155. Next, we explored the effect of differential KDM7A expression on cell differentiation, and cell death and apoptosis after exposure to daunorubicin chemotherapy. For this work we used GFP-labeled miR-155 and YFP-labeled KDM7A lentiviral constructs and labeled control constructs. To examine differentiation we used benzidine staining of hemin-exposed K562 cells transduced with empty control vector (ECV), miR-155, KDM7A, or both constructs. The lowest percentage of benzidine staining, consistent with limited erythroid differentiation, was seen in K562 cells with miR-155 overexpression compared to ECV (28.2% vs. 39.8% positive). This effect on blocked erythroid differentiation was fully reversed with overexpression of KDM7A in miR-155 overexpressing cells (41.4% positive). Confirming these observations, we also observed decreased benzidine staining in hemin exposed K562 cells that were transduced with KDM7A shRNA versus control (28.9% versus 42.7%). Together, these data support that KDM7A plays a role in cell differentiation that is in part controlled by miR-155 expression. Preliminary data also support that re-expression of KDM7A in miR-155 overexpressing cells promotes cell death after exposure to daunorubicin. Further work is ongoing. In conclusion, we have identified a new target of miR-155, KDM7A. Our data suggest that KDM7A plays a role in cell differentiation and that decreased KDM7A expression in AML cells that overexpress miR-155 contributes to blocked differentiation, and may also contribute to resistance to chemotherapy. Disclosures No relevant conflicts of interest to declare.

Distinct Expression Patterns in Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) Characterized by Uniparental Disomy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1193-1193
Author(s):  
Lars Bullinger ◽  
Jan Kronke ◽  
Ursula Botzenhardt ◽  
Sabrina Heinrich ◽  
Katja Urlbauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Dosage ◽  
Expression Patterns ◽  
Uniparental Disomy ◽  
T Test ◽  
Gene Expression Patterns ◽  
Gene Dosage Effect ◽  
Acute Myeloid

Abstract Genome-wide single nucleotide polymorphism (SNP) analyses have revealed uniparental disomy (UPD) to be a common event in cytogenetically normal acute myeloid leukemia (CN-AML) occurring in approximately 20% of cases. Acquired UPD results in copy number neutral loss of heterozygosity (LOH). Comparing matched tumor and germline DNA samples recurrent acquired UPDs affecting chromosomes 11p and 13q were identified. As DNA microarray-based gene expression profiling (GEP) has recently been shown to powerfully capture the molecular heterogeneity of leukemia, we sought to identify gene expression patterns associated with recurrent UPD in CN-AML. We profiled a set of clinically annotated CN-AML specimens (n=66) entered on a multicenter trial for patients <60 years (AMLSG 07-04) which had been characterized by either 50k or 500k Affymetrix SNP microarrays. All cases were analyzed using Affymetrix microarrays (Human Genome U133 Plus 2.0 Arrays). In this data set we investigated 12 UPDs (affecting chromosomes 1p, 2p, 6p, 11p, 13q and 19q) and applied supervised analyses to define gene-expression patterns associated with UPDs on chromosome 11p and 13q. For the case with an acquired UPD on 19q a gene dosage effect could be demonstrated. Genes located in the 36 Mb large UPD region showed a significantly lower average expression (p<0.001; t-test). Similarly, we observed a gene dosage effect in one of the UPDs observed on chromosome 1 (p=0.0097; t-test), whereas for the other UPDs no significant association between LOH and gene expression levels could be identified. Despite small sample numbers supervised analyses revealed a biologically meaningful gene expression signatures associated with acquired UPD 11p and 13q. In accordance with the association of UPD 13q with FLT3-ITD, the UPD13q gene expression signature was enriched for genes associated with FLT3-ITD. The UPD11p expression pattern was characterized by genes found to be down-regulated in CEBPAmut CN-AML cases, such as down-regulation of homeobox genes HOXA9, HOXA10, HOXB2, and MEIS1. Notably, the UPD11p signature was also characterized by the expression of e.g. UGT2B28, P2RX5, PGDS, CAPN1, NDFIP1, and TRIB2, an expression profile that has been shown to be associated with CEBPAmut CN-AML as well as AML cases with epigenetic CEBPA silencing. Thus, our findings represent a starting point to further dissect CN-AML characterized by recurrent UPD, and ongoing analyses will provide additional insights into leukemia biology.

scholarly journals High expression of CD52 mRNA predicts poor prognosis for cytogenetic normal acute myeloid Leukemia patients

2020 ◽  
Author(s):  
Ping Cai ◽  
Wenzhi Cai ◽  
Xiaoyu Xu ◽  
Xiaofei Yang ◽  
Yemin Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Rank Test ◽  
Dna Hypomethylation ◽  
Log Rank Test ◽  
Pathological Mechanism ◽  
High Level ◽  
Acute Myeloid

Abstract Background: The prognosis of cytogenetic normal acute myeloid leukemia (CN-AML) varies. Finding new biomarkers affecting the prognosis of these patients may bring a new strategy for precise classification and treatment. CD52 plays a significant role in chronic lymphocytic leukemia (CLL). However, the potential role of CD52 in CN-AML remains largely elusive. Methods: We analyzed the prognostic role of different expression levels of CD52 in 58 CN-AML from The Cancer Genome Atlas (TCGA) dataset and validated these results with 345 CN-AML patients from Gene Expression Omnibus (GEO) dataset. Results: CN-AML patients with high CD52 mRNA expression had a poorer prognosis compared to low CD52 expression ( event-free survival [EFS], P =0.056; overall survival [OS], P=0.043; log-rank test) and the results was verified by GSE12417 (OS, P=0.020; log-rank test) and GSE71014 (OS, P=0.020; log-rank test). Hematopoietic stem cell transplantation (HSCT) may improve prognosis of patients with CD52 high . Regression analysis shows that the expression level of CD52 (HR=1.503; 95%CI:1.158-1.949 ; P=0.002) is a prognostic factor independent of age (HR=3.045; 95%CI:1.524-6.086; P=0.002) and FLT3 mutation status (HR=2.219; 95%CI:1.123-4.382; P=0.022). CD52 gene expression shows a predictive effect on EFS (1-year survival- area under the curve [AUC]:0.685, 2-year survival-AUC:0.752) and OS (1-year survival-AUC: 0.717, 2-year survival-AUC:0.770). Besides, we also found that there is a significant negative correlation between CD52 mRNA expression and DNA methylation . Accordingly, we speculated that CD52 DNA hypomethylation may responsible for the high level of CD52 mRNA. Functional enrichment analysis of differentially expressed genes in CD52 high and CD52 low suggests that adhesion molecule deregulation maybe also the potential pathological mechanism of CD52. Conclusions: CD52 gene mRNA overexpression is an independent adverse prognostic factor for CN-AML. CD52 DNA hypomethylation may responsible for the high level of CD52 mRNA. Adhesion molecule deregulation maybe potential pathological mechanism of CD52. Whether CD52 monoclonal antibodies play a role in high risk patients need further research.

scholarly journals Distinct gene expression patterns associated with FLT3- and NRAS-activating mutations in acute myeloid leukemia with normal karyotype

Oncogene ◽  
2005 ◽  
Vol 24 (9) ◽  
pp. 1580-1588 ◽  
Author(s):  
Kai Neben ◽  
Susanne Schnittger ◽  
Benedikt Brors ◽  
Björn Tews ◽  
Felix Kokocinski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Patterns ◽  
Normal Karyotype ◽  
Gene Expression Patterns ◽  
Activating Mutations ◽  
Distinct Gene ◽  
Acute Myeloid

Combined Analysis of Valproic Acid Induced MicroRNA and Gene Expression Changes in Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 869-869 ◽  
Author(s):  
Annika C. Russ ◽  
Martin Dugas ◽  
Sonja C. Schmid-Fetzer ◽  
Richard F. Schlenk ◽  
Jonathan R. Pollack ◽  
...  
Keyword(s):  
Gene Expression ◽  
Valproic Acid ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Myeloid Differentiation ◽  
Mrna Cleavage ◽  
Wide Range ◽  
Acute Myeloid

Abstract Inhibitors of histone deacetylases (HDACs) like valproic acid (VPA) display activity in murine leukemia models and induce apoptosis and myeloid differentiation of acute myeloid leukemia (AML) blasts. While recently several studies examined the underlying VPA-mediated mechanisms, until today not many genes have been identified whose expression is altered by VPA treatment. Recently, microRNAs (miRs), a novel abundant class of negative gene regulators, have been shown to control a wide range of biological functions such as proliferation, differentiation and apoptosis by either translational repression or by mRNA cleavage or miR-mediated decay of the respective target mRNA. Furthermore, deregulated miR expression has been associated with various human cancers including leukemia. This led us to investigate whether VPA treatment of AML cells affects miR-expression which in turn might influence the level of miR target genes involved in VPA effects. First, we identified an in vitro miR VPA-response signature by profiling miR expression in 4 different myeloid leukemia cell lines following 48 hours of VPA treatment (Ambion microarray platform comprising 281 human miRs). In parallel, we profiled gene expression by using both cDNA microarrays and Affymetrix U133Aplus2.0 GeneChips. 13 miRs were found to be differentially expressed, 10 miRs were down-regulated and 3 miRs were up-regulated by VPA. Gene expression profiling revealed several hundred differentially regulated genes containing some known VPA influenced targets like e.g. cyclin-dependent kinase inhibitor CDKN1A coding for p21. To correlate miR and gene expression, we next searched for an enrichment of putative miR target genes of the VPA-regulated miRs in the VPA-induced gene expression pattern. Interestingly, there were several candidates for which miR expression in response to VPA inversely correlated with gene expression of the respective targets. These included genes involved in DNA damage checkpoint like e.g. CHEK1 which was found to be down-regulated in response to VPA and which is a predicted target of miR-15a and miR-16, both found to be up-regulated by VPA treatment. In addition, potential miR-targets included genes known to be regulated by HDAC inhibitors in cancer cells like e.g. the homeobox gene HOXA1 found to be up-regulated in response to VPA and being a putative target of miR-99a, found to be down-regulated by VPA. Our study is the first to show that VPA treatment significantly affects expression levels of several miRs in myeloid cell lines, and based on the correlation of VPA-induced miR and gene expression patterns we could identify putative miR-targets that included genes with tumorigenic relevance. While it remains to be determined whether VPA-induced miR-mediated mRNA cleavage or decay of the respective target mRNAs is involved in leukemogenesis, our data nevertheless provide new insights into VPA-induced mechanisms of myeloid differentiation and into deregulated miR expression in leukemia.

Integrative Analysis of NPM1 Mutation-Associated MicroRNA and Gene Expression Signatures Identifies Potential Leukemia-Relevant Genes in Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 363-363
Author(s):  
Annika C Russ ◽  
Sonja C Lück ◽  
Sandrine Sander ◽  
Hartmut Döhner ◽  
Konstanze Döhner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Target Gene ◽  
Target Genes ◽  
Integrative Analysis ◽  
Luciferase Reporter ◽  
Self Renewal ◽  
Npm1 Mutation ◽  
Acute Myeloid

Abstract Abstract 363 MicroRNAs (miRs) have been shown to control a wide range of biological functions such as differentiation, proliferation and apoptosis, either by translational repression, mRNA cleavage or miR mediated decay of the respective target mRNA. Deregulated miR expression has been associated with various human cancers, including acute myeloid leukemia (AML), a disease characterized by the accumulation of acquired genetic alterations in hematopoietic progenitor cells that lead to altered self-renewal, proliferation and differentiation. Mutations of the nucleophosmin (NPM1) gene could be identified as the most common genetic alteration in AML, mainly occurring in cytogenetically normal karyotype (CN-AML) cases. Furthermore, while NPM1 mutated cases show a favorable prognosis (in the absence of FLT3-ITD) and have been shown to possess a distinct gene expression profile (GEP), so far the biology underlying this aberration has still not been fully understood. In previous work, we profiled the miR expression in a cohort of 91 AML cases comprising all major cytogenetic and molecular genetic subgroups. Significance Analysis of Microarrays (SAM) revealed a distinct miR-signature associated with NPM1 mutation (NPM1mut) in CN-AML as also shown by other groups: 66 miRs were differentially expressed in NPM1mut compared to NPM1 wild-type (NPM1wt) cases. The vast majority of these miRs was strongly upregulated in NPM1mut CN-AML, whereas only few miRs were downregulated compared to NPM1wt cases. Therefore, overexpression of a distinct set of miRs seems to be an important characteristic of NPM1mut CN-AML, and the resulting deregulated expression of target genes of these NPM1mut signature miRs might contribute to leukemogenesis. To identify putative target genes of NPM1mut-associated miRs, we performed an integrative analysis of miR-expression and NPM1mut-related gene expression data in our cohort. First, we generated target gene lists for the core 33 overexpressed miRs of the NPM1mut signature by using the miRGator database. This resulted in a theoretical NPM1mut associated GEP. Then, a comparison of the theoretical with the measured NPM1mut GEP was performed in order to find putative targets whose mRNA levels are directly affected by the respective miRs. This approach revealed several promising candidate genes with known implication in tumorigenesis and/or leukemogenesis like APP, CCND1, IRF2, BCL2L1, MLL and KIT. Interestingly, these genes are putative targets of not only one, but several miRs (4 to 15) of the NPM1mut signature, thereby pointing towards a synergistic effect of these miRs. Validation of individual miR-target gene relations was carried out by qRT-PCR in cell lines transfected with the respective miR mimics, supplemented by Western Blot and 3'UTR-luciferase-reporter assays. This validation was successful, not only for already known miR-target gene connections, but also for novel candidates including e.g. CCND1, a cell cycle regulator, and interferon regulatory factor-2 (IRF2). IRF2 is known to show dysregulated expression in the majority of AML cases and has recently been described to be essential for preserving the self-renewal and multilineage differentiation capacity of hematopoietic stem cells (Sato et al., Nat Med 2009). Thus, our approach of combining miR expression information and GEP in NPM1mut CN-AML led to the identification of promising target genes with potential implication in leukemogenesis. Additional functional analyses of relevant miRs and target genes are currently in progress to further illuminate the mechanism of NPM1mut AML pathogenesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals HOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ganqian Zhu ◽  
Huacheng Luo ◽  
Yang Feng ◽  
Olga A. Guryanova ◽  
Jianfeng Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Patterns ◽  
Promoter Regions ◽  
Signature Genes ◽  
Non Coding Rna ◽  
Rna Activation ◽  
Long Non Coding Rna ◽  
Acute Myeloid

AbstractNucleophosmin (NPM1) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c+). NPM1c+ maintains a unique leukemic gene expression program, characterized by activation of HOXA/B clusters and MEIS1 oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c+ controls such gene expression patterns to promote leukemogenesis remain largely unknown. Here, we show that the activation of HOXBLINC, a HOXB locus-associated long non-coding RNA (lncRNA), is a critical downstream mediator of NPM1c+-associated leukemic transcription program and leukemogenesis. HOXBLINC loss attenuates NPM1c+-driven leukemogenesis by rectifying the signature of NPM1c+ leukemic transcription programs. Furthermore, overexpression of HoxBlinc (HoxBlincTg) in mice enhances HSC self-renewal and expands myelopoiesis, leading to the development of AML-like disease, reminiscent of the phenotypes seen in the Npm1 mutant knock-in (Npm1c/+) mice. HoxBlincTg and Npm1c/+ HSPCs share significantly overlapped transcriptome and chromatin structure. Mechanistically, HoxBlinc binds to the promoter regions of NPM1c+ signature genes to control their activation in HoxBlincTg HSPCs, via MLL1 recruitment and promoter H3K4me3 modification. Our study reveals that HOXBLINC lncRNA activation plays an essential oncogenic role in NPM1c+ leukemia. HOXBLINC and its partner MLL1 are potential therapeutic targets for NPM1c+ AML.

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