Subtype-specific regulatory network rewiring in acute myeloid leukemia [Hi-C]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE108303 | 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 | GSE108246 | 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: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: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.
2010-07-01 | GSE18018 | GEO
Project description:Effectively targeting leukemia-initiating cells (LIC) in FLT3-internal-tandem-duplication (ITD)-mutated acute myeloid leukemia (AML) remains a crucial goal for achievement of cure. FLT3 tyrosine kinase inhibitors (TKI) have limited impact as single agents and have thus far been unable to eradicate LIC enriched in the CD34+CD38- bone marrow compartment and protected by contact with niche cells.Using primary AML samples in vitro as well as in an in vivo xenograft model, we investigated whether combining the novel FLT3-selective TKI crenolanib with the hypomethylating agent azacitidine (AZA) can eliminate LIC in FLT3-ITD+ AML and determined whether efficacy of this combination is dependent on coexisting genetic mutations in DNMT3A, NPM1 and TET2. Our data show that crenolanib as a single agent was unable to target FLT3-ITD+ LIC in contact with niche cells while the addition of AZA overcame stromal protection and resulted in dramatically reduced clonogenic capacity of FLT3-ITD+ LIC in vitro as well as severely impaired engraftment capacity of FLT3-ITD+ LIC in NSG mice. Strikingly, FLT3-mutated AML samples harboring concurrent TET2 mutations were completely resistant to crenolanib as a single agent. Mutations in DNMT3A or NPM1 had no influence on response to crenolanib while DNMT3A mutations conferred increased sensitivity of FLT3-ITD+ LIC to AZA. Our data suggest that response to crenolanib or AZA as single agents in FLT3-ITD+ AML is highly dependent on coexisting mutations in epigenetic regulators. However, the combination of AZA + crenolanib effectively eliminated FLT3-ITD+ LIC irrespective of additional mutations in NPM1, DNMT3A or TET2.
2017-04-03 | GSE86021 | GEO
Project description:We studied gene expression profiles from 65 patients with CN-AML, who all had wild-type NPM1 and no FLT3-ITD. We identified an ASXL1 mutation-associated gene expression signature by comparing 26 ASXL1-mutated and 39 ASXL1-wild type patients. Only NPM1 wild type/FLT3-ITD-negative patients were included in this analysis to avoid potential confounding due to the effects of these two mutations on gene expression.
2012-10-10 | E-TABM-1208 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) carrying NPM1 mutations and cytoplasmic nucleophosmin (NPMc+ AML) accounts for about one-third of adult AML and shows distinct features, including a unique gene expression profile. MicroRNAs (miRNAs) are small noncoding RNAs of 19-25 nucleotides in length that have been linked to the development of cancer. Here, we investigated the role of miRNAs in the biology of NPMc+ AML. The miRNA expression was evaluated in 85 adult de novo AML patients characterized for subcellular localization/mutation status of NPM1 and FLT3 mutations using a custom microarray platform. Data were analyzed by using univariate t test within BRB tools. We identified a strong miRNA signature that distinguishes NPMc+ mutated (n = 55) from the cytoplasmic-negative (NPM1 unmutated) cases (n = 30) and includes the up-regulation of miR-10a, miR-10b, several let-7 and miR-29 family members. Many of the down-regulated miRNAs including miR-204 and miR-128a are predicted to target several HOX genes. Indeed, we confirmed that miR-204 targets HOXA10 and MEIS1, suggesting that the HOX up-regulation observed in NPMc+ AML may be due in part by loss of HOX regulators-miRNAs. FLT3-ITD+ samples were characterized by up-regulation of miR-155. Further experiments demonstrated that the up-regulation of miR-155 was independent from FLT3 signaling. Our results identify a unique miRNA signature associated with NPMc+ AML and provide evidence that support a role for miRNAs in the regulation of HOX genes in this leukemia subtype. Moreover, we found that miR-155 was strongly but independently associated with FLT3-ITD mutations.
2008-03-14 | E-TABM-429 | 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:Acute myeloid leukemia (AML) is a heterogeneous disease and AML with normal karyotype (AML-NK) is categorized as an intermediate-risk group. Over the past years molecular analyses successfully identified biomarkers that will further allow to dissecting clinically meaningful subgroups in this disease. Thus far, somatic mutations were identified which elucidate the disturbance of cellular growth, proliferation, and differentiation processes in hematopoietic progenitor cells. In AML-NK, acquired gene mutations with prognostic relevance were identified for FLT3, CEBPA, and NPM1. FLT3-ITD mutations were associated with short relapse-free and overall survival, while mutations in CEBPA or NPM1 (without concomitant FLT3-ITD) had a more favorable outcome. Here, we present a multicenter study investigating gene expression profiles of 251 cases of de novo AML-NK. In three centers whole-genome microarray analyses were performed to delineate robust and common expression signatures for molecular markers in AML-NK. All 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 (Dresden, n=78; Munich, n=97; Ulm, n=77). Each laboratory performed its routine diagnostic algorithms, including the characterization of molecular markers.
2009-12-31 | E-GEOD-15434 | 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.
2009-06-01 | GSE16015 | GEO