Whole Genome sequencing of a normal karyotype AML cell line
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE40199 | GEO | 2013/12/31
SECONDARY ACCESSION(S): PRJNA173077
REPOSITORIES: GEO
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Project description:Normal Karyotype acute myeloid leukemia (NK-AML) represents approximately 50% of all cases of AML which patients develop. Most AML cell lines are highly abnormal and therefore not good models for investigating NK-AML biology a novel AML cell line, CG-SH, was recently estabished and here we characterize the gene expression and mutations present through high-throughput sequencing of RNA and genomic DNA using a HiSeq 2000 The overall design of the experiment was to characterize, at single base pair resolution, all of the genetic defects present in a novel normal karyotype cell line, CG-SH
2013-12-31 | E-GEOD-40199 | biostudies-arrayexpress
Project description:Acute myeloid leukemia with normal karyotype (NK-AML) represents a cytogenetic grouping with intermediate prognosis but substantial molecular and clinical heterogeneity. Within this subgroup, presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutation predicts less favorable outcome. The goal of our study was to discover gene-expression patterns correlated with FLT3-ITD mutation, and to evaluate the utility of a FLT3 signature for prognostication. The dataset comprises gene-expression profiles of 137 normal karyotype acute myeloid leukemia (NK-AML) specimens carried out using Stanford cDNA microarrays, to accompany the study of L Bullinger et al. For each array, Channel 2 represents Cy5-labeled NK-AML RNA, and Channel 1 Cy3-labeled universal reference RNA. Keywords: Logical Set DNA microarrays were used to profile gene expression in a training set of 65 NK-AML cases. Supervised analysis was applied to build a gene expression-based predictor of FLT3-ITD mutation status. The predictor was then evaluated by classifying expression profiles from an independent test set of 72 NK-AML cases.
2008-02-27 | E-GEOD-8043 | biostudies-arrayexpress
Project description:Acute myeloid leukemia with normal karyotype (NK-AML) represents a cytogenetic grouping with intermediate prognosis but substantial molecular and clinical heterogeneity. Within this subgroup, presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutation predicts less favorable outcome. The goal of our study was to discover gene-expression patterns correlated with FLT3-ITD mutation, and to evaluate the utility of a FLT3 signature for prognostication. The dataset comprises gene-expression profiles of 137 normal karyotype acute myeloid leukemia (NK-AML) specimens carried out using Stanford cDNA microarrays, to accompany the study of L Bullinger et al. For each array, Channel 2 represents Cy5-labeled NK-AML RNA, and Channel 1 Cy3-labeled universal reference RNA. Keywords: Logical Set
2008-02-28 | GSE8043 | GEO
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.
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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.
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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 AML-NK. In three centers whole-genome microarray analyses were performed to delineate robust and common expression signatures for molecular markers in AML-NK.
2010-01-01 | GSE15434 | GEO
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.
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Project description:Acute myeloid leukemia with complex karyotype (CK-AML) is characterized by three or more chromosomal aberrations, and comprises 10–12% of AML patients. It is associated with complex chromosomal rearrangements, intra-tumor heterogeneity, therapy resistance and poor overall survival. We aimed to transcriptionally characterize CK-AML by performing RNA sequencing on blasts from 4 CK-AML patient samples.
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Project description:More than 40% of patients with AML have a normal karyotype and are included in the intermediate prognostic group, in which risk classification is currently poor defined and more molecular markers are needed to achieve treatment stratification. EVI1 overexpression (OE) has been reported to discriminate in this group those with a worse prognosis. The EVI1 mice homolog has a role in the HSC proliferation through Gata2 expression, therefore, GATA2, a transcription factor with a relevant role in hematopoiesis, could be a candidate gene in the leukemogenic transformation in AML in patients with normal karyotype, and in other subgroups. GATA2 OE was detected in 46% of cases with normal karyotype, and was more frequent among samples with FLT3-ITD (p=0.0021), especially among the AML-M1 cases. We found a mutational pattern FLT3-ITD/GATA2-OE/WT1-OE that could define a subgroup of patients with normal karyotype and AML-M1, with a different gene expression array pattern and a poor prognosis. Our results show that GATA2 OE is a common event in AML cases with normal karyotype (46%). The deregulation of the expression of the GATA2 transcription factor would lead to a hematopoietic differentiation impairs, focusing GATA2 as a candidate gene that fits in the cooperating model for the multistep pathogenesis that causes AML transformation. Keywords: Disease state analysis
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Project description:AML with complex karyotype (CK-AML) is characterized by a high frequency of TP53 alteration (loss and/or mutation). TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs. 6.16; P<.0001), and by a higher frequency of specific copy number alterations, such as -5/5q-, -7/7q-, -16/16q-, -18/18q-, +1/+1p, and +11/+11q/amp11q13~25; among CK-AML, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.
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