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 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

Decitabine Response Associated Gene Expression Patterns In Acute Myeloid Leukemia (AML)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3756-3756 ◽  
Author(s):  
Stephan R Bohl ◽  
Rainer Claus ◽  
Anna Dolnik ◽  
Richard F. Schlenk ◽  
Konstanze Döhner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Acute Myeloid Leukemia ◽  
Immune System ◽  
Cell Surface ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Acute Myeloid

Abstract The hypomethylating agent decitabine (DAC) represents a therapeutic option for acute myeloid leukemia (AML) patients who are not eligible for an intensive treatment regime. However, there are no biomarkers available yet that can predict patients who will likely benefit from this epigenetic therapy. Therefore, we executed a gene expression analysis prior to the treatment of patients with DAC in order to evaluate gene expression patterns associated with response to DAC that ultimately might be used to predict DAC outcome. Patients had been entered in a multicenter phase II trial of DAC as first-line treatment of older AML patients judged unfit for induction chemotherapy (Lübbert et al. Haematologica 2011; NCT00866073). Gene expression was profiled in selected DAC responders (n=17) and non-responders (n=19; non-response was defined as stable disease or progressive disease). These groups did not show significant differences regarding age, gender, performance status, blast counts and cytogenetics. Supervised data analysis strategies were applied to identify genes and gene patterns associated with DAC response. While the study cohort comprised a heterogeneous group of AML patients, a class comparison analysis nevertheless could reveal a DAC response associated gene pattern comprising 301 genes at a significance level of p<0.05. This signature was enriched for genes belonging to pathways that are essential in immune response and tumor suppressor function. Among these genes that were significantly associated with no DAC response included IFI44L, IFI27, PDK4, MX1, FAS, and ITGB2; in contrast to SLC24A3, MUM1, TNFSF9, DBN1, ABAT, and DDX52, which were significantly higher expressed in patients that showed response to DAC treatment. Significantly over-expressed in the DAC non-responder group, the immune and inflammation-related genes IFI44L and IFI27 might reflect a hyperstimulated, but insufficient immune system as has been recently shown in myelofibrosis. As DAC was shown to have the capability to induce cancer testis antigens, thereby generating an efficient immune response with tumor cell lysis by CD8+ T-lymphocytes, an impaired immune system may prevent response to DAC. Furthermore, the non-response signature contained known poor prognostic markers such as PDK4, which has been associated with EVI1 and FLT3-ITD mediated signaling. In addition, we observed high expression of MX1 and FAS in the non-response group. Notably, both genes have been shown to be repressed by promoter hypermethylation in distinct AML subtypes and DAC treatment was able to upregulate their expression levels. In contrast, high pre-treatment expression levels might indicate that in the respective AML cases deregulated promotor methylation might not be the prominent pathomechanism, and thus these cases might less likely benefit from DAC treatment. Finally, we found ITGB2, encoding for an integral cell-surface protein participating in cell-surface mediated signaling, associated with DAC resistance. As recently ITGB3, another member of this integrin protein family, was shown mandatory for leukemogenesis, but not relevant for normal hematopoiesis, high expression of ITGB2 might also play a role in AML and point to leukemias where epigenetic deregulation at the DNA level seems to be a less prone pathomechanism. Among the group of genes linked with response to DAC treatment TNFSF9 can act as cytotoxic leukemic specific T-cell inducer, which has previously been correlated with unfavorable AML subtypes and poor outcome. However, due to the immunomodulation of DAC it seems that the poor prognostic impact of TNFSF9 might be overcome by DAC, thereby rendering TNFSF9 a positive marker for DAC response. In accordance, we found that several genes of the 4-1BB-dependent immune response pathway, including TNFSF9, were more highly expressed in DAC responding patients. Finally, MUM1 encodes also a gene important for interferon dependent immune response, thereby further underscoring a potential immunomodulation effect of DAC. In summary, we were able to elucidate a gene signature which could be used to predict response to DAC treatment in AML. While this gene expression pattern included many genes involved in the immune response, thereby suggesting that the DAC treatment effect is at least in part depending on immunomodulatory effects, further studies are warranted to evaluate the respective markers in larger AML cohorts. Disclosures: Schlenk: Amgen: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Chugai: Research Funding; Ambit: Honoraria.

scholarly journals Gene expression patterns in acute myeloid leukemia correlate with centrosome aberrations and numerical chromosome changes

Oncogene ◽  
2004 ◽  
Vol 23 (13) ◽  
pp. 2379-2384 ◽  
Author(s):  
Kai Neben ◽  
Björn Tews ◽  
Gunnar Wrobel ◽  
Meinhard Hahn ◽  
Felix Kokocinski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Numerical Chromosome ◽  
Acute Myeloid

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.

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 &lt; 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.

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 Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia

Blood ◽  
1996 ◽  
Vol 87 (8) ◽  
pp. 3395-3403 ◽  
Author(s):  
JW Taub ◽  
LH Matherly ◽  
ML Stout ◽  
SA Buck ◽  
JG Gurney ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Down Syndrome ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Gene Dosage ◽  
Chromosome 21 ◽  
Event Free Survival ◽  
Gene Dosage Effect ◽  
Free Survival ◽  
Acute Myeloid

Down syndrome (DS) children with acute myeloid leukemia (AML) have significantly higher event-free survival (EFS) rates compared with non- DS children when treated with protocols containing 1-beta-D- arabinofuranosylcytosine (ara-C). Sensitivity and metabolism of ara-C was examined in myeloblasts from DS and non-DS patients with AML, DS infants with the transient myeloproliferative disorder, and Epstein- Barr Virus (EBV) transformed lymphoblastoid cell lines with and without trisomy 21. DS myeloblasts were approximately 10-fold more sensitive to ara-C (measured by the 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) colorimetric sensitivity assay), compared with non-DS myeloblasts, following exposure to ara-C for 72 hours. Mean levels of l-beta-D-arabinofuranosylcytosine 5′-triphosphate (ara-CTP) were significantly higher in DS myeloblasts compared with non-DS myeloblasts after incubation with 5 micromol/L ara-C (621.4 v 228.4 pmol/mg protein). DS cell lines also generated higher levels of ara-CTP compared with cell lines with diploid chromosome numbers (66.5 v 13.6 pmol/mg protein and 137.6 v 41.7 pmol/mg protein at 1 and 5 micromol/L ara-C, respectively). Elevated ara-CTP levels in the DS cells were accompanied by slightly lower levels of endogenous deoxycytidine triphosphate (dCTP) pools, slightly greater extent of ara-C incorporation into DNA, and increased relative numbers of double strand DNA strand breaks. There were no significant differences in the cell cycle distributions of DS and non-DS cells. These in vitro studies support our hypothesis that enhanced metabolism of ara-C in DS cells may be a contributing factor to the superior survival rate of DS children with AML and is possibly based on a gene dosage effect of genes localized to chromosome 21 including cystathionine-beta-synthase. Further study of the mechanisms (ie, alterations in dCTP pools and DNA methylation) involved may lead to improvements in the treatment of all AML patients.

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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