Subtype-specific regulatory network rewiring in acute myeloid leukemia [DNase-Hypersensitivity]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE108246 | GEO | 2018/09/20
REPOSITORIES: GEO
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Project description:Acute myeloid leukemia is a heterogeneous disease which is subdivided into different categories defined by disease-causing mutations in transcription factors, epigenetic regulators and signalling molecules. How different mutant regulators establish AML-specific transcriptional networks is unclear. Here we performed a comprehensive analysis of mutation-specific sets of cis-regulatory elements driving gene expression in AML blast cells from a carefully selected group of patients with alterations in genes encoding transcription factors (RUNX1, CEBPA) and signalling molecules (FTL3-ITD, RAS, NPM1). We show that each mutant regulator establishes a specific transcriptional and signalling network unrelated to normal cells driving the expression of unique sets of genes required for AML survival.
2018-09-20 | GSE108303 | GEO
Project description:Acute myeloid leukemia is a heterogeneous disease which is subdivided into different categories defined by disease-causing mutations in transcription factors, epigenetic regulators and signalling molecules. How different mutant regulators establish AML-specific transcriptional networks is unclear. Here we performed a comprehensive analysis of mutation-specific sets of cis-regulatory elements driving gene expression in AML blast cells from a carefully selected group of patients with alterations in genes encoding transcription factors (RUNX1, CEBPA) and signalling molecules (FTL3-ITD, RAS, NPM1). We show that each mutant regulator establishes a specific transcriptional and signalling network unrelated to normal cells driving the expression of unique sets of genes required for AML survival.
2018-09-20 | GSE108266 | GEO
Project description:Acute Myeloid Leukemia (AML) represents a heterogeneous group of hematological malignancies. The t(6;9)(p23;q34) translocation, giving rise to the DEK::NUP214 fusion protein, is a rare mutation which produces a highly aggressive AML associated with extremely poor prognosis. Here, we utilise genome-wide chromatin accessibility to elucidate how a normal gene regulatory networks is disrupted by DEK::NUP214. We find that DEK::NUP214 AML forms a specific GRN related to that of mutant NPM1 AML, but also displays an elevated leukemic stem cell signature, suggesting both similar and unique therapeutic vulnerabilities.
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Project description:Purpose: CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal AML (CN-AML). Patients and Methods: 467 homogeneously treated CN-AML patients were subdivided into moCEBPA, biCEBPA and wildtype (wt) CEBPA patients. The subgroups were analyzed for clinical parameters and for additional mutations in the NPM1, FLT3 and MLL genes. Furthermore, we obtained gene expression profiles (GEP) for a subgroup of 61 patients using oligonucleotide microarrays.
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Project description:Multilineage dysplasia (MLD) has no impact on biological, clinico-pathological and prognostic features of AML with mutated nucleophosmin (NPM1) NPM1-mutated AML is a provisional entity in the WHO-2008 classification of myeloid neoplasms. The significance of concomitant multilineage dysplasia (MLD) in NPM1-mutated AML is unclear. Thus, in the WHO-2008 classification, NPM1-mutated AML with MLD is classified as AML with myelodysplasia(MD)-related changes. We evaluated the MLD impact in 378 NPM1-mutated AML patients. MLD was found in about 25% cases. Except for a lower WBC and FLT3-ITD incidence in MLD+ group, no significant differences were observed in age, sex, cytogenetics and FLT3-TKD between NPM1-mutated AML with and without MLD. Notably, NPM1-mutated AML with/without MLD showed overlapping immunophenotype (CD34-negativity) and GEP (CD34 downregulation and HOX genes upregulation). Moreover, OS and EFS did not differ among NPM1-mutated AML patients, independently of whether they carried or not MLD, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Lack of MLD impact on survival was confirmed by multivariate analysis that highlighted FLT3-ITD as the most significant prognostic parameter in NPM1-mutated AML. Our findings indicate that NPM1 mutations rather than MLD dictate the distinctive features of NPM1-mutated AML. Thus, irrespective of MLD, NPM1-mutated AML should be considered as one disease entity clearly distinct from AML with MD-related changes. These findings have important diagnostic and prognostic implications in AML. All bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation. 48 samples
2010-07-30 | E-GEOD-18018 | biostudies-arrayexpress
Project description:Somatic mutations in cancer are a potential source of cancer specific neoantigens. Acute myeloid leukemia (AML) has common recurrent mutations shared between patients in addition to private mutations specific to individuals. We hypothesized that neoantigens derived from recurrent shared mutations would be attractive targets for future immunotherapy and sought to study the Class I and II HLA ligandomes of thirteen primary AML tumor samples and two AML cell lines (OCI-AML3 and MV4-11) using mass spectrometry. We identified two endogenous, mutation-bearing HLA Class I ligands from NPM1, which are predicted to bind the common HLA haplotypes, HLA-A*03:01 and HLA-A*02:01 respectively. We further derived CD8+ T cells from healthy donor peripheral blood samples which bound mutant-peptide loaded A*03:01 and A*02:01 tetramers, suggesting a new source of NPM1 mutation-specific T cell receptors (TCRs) for future evaluation. Since NPM1 is mutated in approximately one-third of patients with AML, the finding of endogenous NPM1 neoantigens supports future studies evaluating immunotherapeutic approaches against this target, for this subset of patients with AML.
2019-07-17 | PXD012083 | Pride
Project description:Multilineage dysplasia (MLD) has no impact on biological, clinico-pathological and prognostic features of AML with mutated nucleophosmin (NPM1) NPM1-mutated AML is a provisional entity in the WHO-2008 classification of myeloid neoplasms. The significance of concomitant multilineage dysplasia (MLD) in NPM1-mutated AML is unclear. Thus, in the WHO-2008 classification, NPM1-mutated AML with MLD is classified as AML with myelodysplasia(MD)-related changes. We evaluated the MLD impact in 378 NPM1-mutated AML patients. MLD was found in about 25% cases. Except for a lower WBC and FLT3-ITD incidence in MLD+ group, no significant differences were observed in age, sex, cytogenetics and FLT3-TKD between NPM1-mutated AML with and without MLD. Notably, NPM1-mutated AML with/without MLD showed overlapping immunophenotype (CD34-negativity) and GEP (CD34 downregulation and HOX genes upregulation). Moreover, OS and EFS did not differ among NPM1-mutated AML patients, independently of whether they carried or not MLD, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Lack of MLD impact on survival was confirmed by multivariate analysis that highlighted FLT3-ITD as the most significant prognostic parameter in NPM1-mutated AML. Our findings indicate that NPM1 mutations rather than MLD dictate the distinctive features of NPM1-mutated AML. Thus, irrespective of MLD, NPM1-mutated AML should be considered as one disease entity clearly distinct from AML with MD-related changes. These findings have important diagnostic and prognostic implications in AML.
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2016-02-26 | E-GEOD-69095 | biostudies-arrayexpress
Project description:AML with mutated NPM1 usually carries normal karyotype (NK) but it may harbor chromosomal aberrations whose significance remains unclear. We addressed this question in 631 AML patients with mutated/cytoplasmic NPM1. An abnormal karyotype (AK) was present in 93/631 cases (14.7%), the most frequent abnormalities being +8, +4, -Y, del(9q), +21. Chromosome aberrations in NPM1-mutated AML were similar to, but occurred less frequently than additional chromosome changes found in other AML with recurrent cytogenetic abnormalities according to WHO classification. Four of the 31 NPM1-mutated AML patients karyotyped at different time points had NK at diagnosis but AK at relapse: del(9q) (n=2), t(2;11) (n=1), inv(12) (n=1). NPM1-mutated AML with NK or AK showed overlapping morphological, immunophenotypic (CD34-negativity) and gene expression profile (downregulation of CD34 and upregulation of HOX genes). No difference in survival was observed among NPM1-mutated AML patients independently of whether they carried a normal or abnormal karyotype, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Findings in our patients point to chromosomal aberrations as secondary events, reinforce the concept that NPM1 mutation is a founder genetic lesion and indicate that NPM1-mutated AML should be clinically handled as one entity, irrespective of the karyotype. All bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation.
2009-06-01 | E-GEOD-16015 | biostudies-arrayexpress
Project description:Purpose: CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal AML (CN-AML). Patients and Methods: 467 homogeneously treated CN-AML patients were subdivided into moCEBPA, biCEBPA and wildtype (wt) CEBPA patients. The subgroups were analyzed for clinical parameters and for additional mutations in the NPM1, FLT3 and MLL genes. Furthermore, we obtained gene expression profiles (GEP) for a subgroup of 61 patients using oligonucleotide microarrays. 61 bone-marrow samples from CN-AML patients were analyzed using Affymetrix HG-U133 oligonucleotide microarrays (Affymetrix, Santa Clara, CA). Sample preparation, hybridization and image acquisition were performed according to standard Affymetrix protocols. Custom chip definition files based on the GeneAnnot database were used for data analysis (Ferrari et al, BMC Bioinformatics 8:446). The twilight algorithm was used to comapre gene expression profiles of patients with wildtype CEBPA and mono- and biallelic CEBPA mutations.
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