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  • 1
    Publication Date: 2009-11-20
    Description: Abstract 1275 Poster Board I-297 Core binding factor (CBF) leukemias, characterized by translocations t(8;21) or inv(16)/t(16;16) targeting the core binding factor, constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, 40-50% of patients relapse, and the current classification system does not fully reflect the heterogeneity existing within the cytogenetic subgroups. Therefore, illuminating the biological mechanisms underlying these differences is important for an optimization of therapy. Previously, gene expression profiling (GEP) revealed two distinct CBF leukemia subgroups displaying significant outcome differences (Bullinger et al., Blood 2007). In order to further characterize these GEP defined CBF subgroups, we again used gene expression profiles to identify cell line models similar to the respective CBF cohorts. Treatment of these cell lines with cytarabine (araC) revealed a differential response to the drug as expected based on the expression patterns reflecting the CBF subgroups. In accordance, the cell lines resembling the inferior outcome CBF cohort (ME-1, MONO-MAC-1, OCI-AML2) were less sensitive to araC than those modeling the good prognostic subgroup (Kasumi-1, HEL, MV4-11). A previous gene set enrichment analysis had identified the pathways Caspase cascade in apoptosis and Role of mitochondria in apoptotic signaling among the most significant differentially regulated BioCarta pathways distinguishing the two CBF leukemia subgroups. Thus, we concluded that those pathways might be interesting targets for specific intervention, as deregulated apoptosis underlying the distinct subgroups should also result in a subgroup specific sensitivity to apoptotic stimuli. Therefore, we treated our model cell lines with the Smac mimetic BV6, which antagonizes inhibitor of apoptosis (IAP) proteins that are differentially expressed among our CBF cohorts. In general, sensitivity to BV6 treatment was higher in the cell lines corresponding to the subgroup with good outcome. Time-course experiments with the CBF leukemia cell line Kasumi-1 suggested a role for caspases in this response. Interestingly, combination treatment of araC and BV6 in Kasumi-1 showed a synergistic effect of these drugs, with the underlying mechanisms being currently further investigated. Based on the promising sensitivity to BV6 treatment in some cell lines, we next treated mononuclear cells (mostly leukemic blasts) derived from newly diagnosed AML patients with BV6 in vitro to evaluate BV6 potency in primary leukemia samples. Interestingly, in vitro BV6 treatment also discriminated AML cases into two distinct populations. Most patient samples were sensitive to BV6 monotherapy, but about one-third of cases were resistant even at higher BV6 dosage. GEP of BV6 sensitive patients (at 24h following either BV6 or DMSO treatment) provided insights into BV6-induced pathway alterations in the primary AML patient samples, which included apoptosis-related pathways. In contrast to the BV6 sensitive patients, GEP analyses of BV6 resistant cases revealed no differential regulation of apoptosis-related pathways in this cohort. These results provide evidence that targeting deregulated apoptosis pathways by Smac mimetics might represent a promising new therapeutic approach in AML and that GEP might be used to predict response to therapy, thereby enabling novel individual risk-adapted therapeutic approaches. Disclosures Vucic: Genentech, Inc.: Employment. Deshayes:Genentech, Inc.: Employment.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2008-11-16
    Description: 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
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 3
    Publication Date: 2009-11-20
    Description: Abstract 2391 Poster Board II-368 Alternative mRNA splicing represents an effective mechanism of regulating gene function as well as a key element to increase the coding capacity of the human genome. Today, an increasing number of reports illustrates that aberrant splicing events can contribute to human disease and that alterations in the splicing machinery are common and functionally important for cancer development. Aberrant splice forms can for example have genome-wide effects by deregulating key signaling pathways. However, for most of the aberrant mRNA transcripts detected it remains unclear whether they directly contribute to the malignant phenotype or just represent a by-product of cellular transformation. Thus, more comprehensive analyses of the transcriptome splicing are warranted in order to get novel insights into the biology underlying malignancies like, e.g., acute myeloid leukemia (AML). Here, we performed a genome-wide screening of splicing events in AML using the Exon microarray platform GeneChip Human Exon 1.0 ST (Affymetrix). We analyzed forty AML cases with complex karyotypes and twenty Core Binding Factor (CBF) AML cases (entered on a multicenter trial for patients
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  • 4
    Publication Date: 2009-11-20
    Description: Abstract 2613 Poster Board II-589 Cytogenetically normal acute myeloid leukemia (CN-AML) represents a biologically and clinically heterogeneous group. During recent years novel molecular markers like FLT3, CEBPA and NPM1 gene mutations as well as deregulated expression of single genes such as EVI1, MN1, ERG and BAALC have been identified that provide important prognostic information in CN-AML. Furthermore, DNA microarray-based gene expression profiling (GEP) has been shown to capture the molecular heterogeneity of leukemia and has been applied to build clinical outcome predictors in CN-AML. In this study, we wanted to assess whether GEP based outcome prediction using novel biostatistical approaches applied to large gene expression data sets could refine previous findings. First we profiled gene expression in a large set of clinically well annotated CN-AML (entered on a multicenter trial for patients
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
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  • 5
    Publication Date: 2008-11-16
    Description: Cytogenetically normal acute myeloid leukemia (CN-AML) comprises a biologically and clinically heterogeneous group of AML. In the past years, molecular markers like FLT3, CEBPA and NPM1 gene mutations have been identified in CN-AML, and the presence of such mutations carries important prognostic information. Furthermore, DNA microarray-based gene expression profiling (GEP) has been shown to capture the molecular heterogeneity of cancers, and has been applied to build classifiers and clinical outcome predictors in AML. While prior studies have defined gene expression patterns associated with NPM1, CEBPA, and FLT3, we assessed the clinical relevance of gene signatures. We profiled a large set of clinically well annotated CN-AML specimens (n=296 entered on two multicenter trials for patients 95% in leave-one-out cross validated classification. Prediction of FLT3-ITD or CEBPA mutation performed less well with accuracies of 80% and 73%, respectively. However, for both CEBPA and FLT3-ITD the predicted mutation class labels performed slightly better than the marker itself with regard to the prognostic impact on overall survival (CEPBA: p=0.006 vs. p=0.007, FLT3-ITD p=9.57e-06 vs. p=5.11e-05; logrank test). In addition, using LASSO we also could define a signature associated with event free survival (EFS) in the cases from the AMLSG 07-04 trial. Adjusted for age, NPM1, and FLT3-ITD mutational status this signature was significantly associated with EFS (p=0.005; Wald test), and validation in our independent cDNA data set also provided significant prognostic information (p=0.02; Wald test). Thus, GEP-based classification of CN-AML might help to identify alternative genetic changes that either phenocopy or block the effects of common molecular aberrations. Furthermore, gene expression patterns of yet unknown aberrations are reflected in prognostic signatures. Therefore, signature genes also provide a starting point to dissect “mutations” pathways, and our findings underscore the potential clinical utility of a gene expression based measure in CN-AML.
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    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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