Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Whole-Genome Sequencing of Acute Myeloid Leukemia

ABSTRACT:

We used massively parallel sequencing technology to sequence the genomic DNA of tumor cells (leukemic bone marrow) and normal cells (skin biopsy) obtained from patients with Acute Myeloid Leukemia (AML). Patients had either de novo AML (AML with no prior diagnosis of a hematologic disease or exposure to chemotherapy), secondary AML (occurring after a prior diagnosis of myelodysplastic syndromes (MDS)), or therapy-related AML (occurring after exposure to prior chemotherapy). We identified somatic mutations in the tumor genomes, including single nucleotide variants, insertions, deletions, and structural variants.

PROVIDER: phs000159.v4.p2 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Json Xml

Publications

Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes.

Graubert Timothy A TA Shen Dong D Ding Li L Okeyo-Owuor Theresa T Lunn Cara L CL Shao Jin J Krysiak Kilannin K Harris Christopher C CC Koboldt Daniel C DC Larson David E DE McLellan Michael D MD Dooling David J DJ Abbott Rachel M RM Fulton Robert S RS Schmidt Heather H Kalicki-Veizer Joelle J O'Laughlin Michelle M Grillot Marcus M Baty Jack J Heath Sharon S Frater John L JL Nasim Talat T Link Daniel C DC Tomasson Michael H MH Westervelt Peter P DiPersio John F JF Mardis Elaine R ER Ley Timothy J TJ Wilson Richard K RK Walter Matthew J MJ

Nature genetics 20111211 1

Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in ...[more]

PMID: 22158538

Publication: 1/7

Similar Datasets

Whole-Genome Sequencing of Acute Myeloid Leukemia

Project description:<p>We used massively parallel sequencing technology to sequence the genomic DNA of tumor cells (leukemic bone marrow) and normal cells (skin biopsy) obtained from patients with Acute Myeloid Leukemia (AML). Patients had either de novo AML (AML with no prior diagnosis of a hematologic disease or exposure to chemotherapy), secondary AML (occurring after a prior diagnosis of myelodysplastic syndromes (MDS)), or therapy-related AML (occurring after exposure to prior chemotherapy). We identified somatic mutations in the tumor genomes, including single nucleotide variants, insertions, deletions, and structural variants.</p>

| phs000159 | dbGaP

Phosphoproteomic profiling of Acute Myeloid Leukaemia

Project description:Acute Myeloid Leukaemia (AML) carries a 5 year survival rate of just 24%. Toxic chemotherapy regimens remain the backbone of standard of care for AML. The FLT3 tyrosine kinase is a recognised AML oncogene, with FLT3 activating mutations occurring in approximately one third of all AML patients. However, therapeutic targeting of FLT3 has proven difficult as monotherapy, with the development of drug resistance and relapse. Characterisation of the signalling pathways regulated by mutant FLT3 is required to identify better therapeutic strategies.

2019-12-20 | MSV000084730 | MassIVE

Gene expression profiles associated with pediatric relapsed AML

Project description:In high income countries 90% of the patients achieve complete remission after induction chemotherapy. However, 30-40% of these patients suffer from relapse. These patients face a dismal prognosis, as the majority (>60%) of relapsed patients die within 5 years. As a result, outcome for pediatric acute myeloid leukemia (AML) patients remains poor and has stabilized over the past 15 years. To prevent or better treat relapse of AML is the best option to improve outcome. Despite patient specific differences, most patients do respond to initial therapy. This suggests that at relapse, mechanisms are active that cause the altered response to chemotherapy. Detailed understanding of mechanisms that cause relapse remain largely elusive. To gain insight in the molecular pathways that characterize relapsed AML, we performed genome wide gene expression profiling on paired initial diagnosis and relapsed AML samples of 23 pediatric AML patients. We used pathway analysis to find which molecular pathways are involved in altered gene expression between diagnosis and relapse samples of individual AML patients. 23 paired diagnosis and relapse bone marrow or peripheral blood samples were collected and cryo-preserved. They were later thawed and processed for hybridization to Affymetrix U133 Plus 2.0 arrays.

2015-05-07 | E-GEOD-52891 | biostudies-arrayexpress

Expression analysis of Mll3 knockdown p53-/- HSPC vs. control p53-/- HSPC

Project description:Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of specific tumor suppressors on 7q remains elusive. Using RNAi and CRISPR/Cas9 approaches, we show that a ~50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3 suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor, and suggests a therapeutic option for this aggressive disease. Total RNA obtained from sorted lin-ckit+ hematopoietic stem and progenitor cells of recipient mice transplanted with shRen;p53-/- or shMll3;p53-/- cells at 6 weeks after transplant

2014-03-19 | E-GEOD-54313 | biostudies-arrayexpress

Loss of DKM6A confers drug resistance in acute myeloid leukemia (ChIP-seq of AML cell lines K562 and THP-1)

Project description:Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm resulting from the malignant transformation of myeloid progenitors. Despite intensive chemotherapy leading to initial treatment responses, relapse caused by intrinsic or acquired drug resistance represents a major challenge. Here, we report that histone 3 lysine 27 demethylase KDM6A (UTX) is targeted by inactivating mutations and mutation-independent regulation in relapsed AML. Analyses of matched diagnosis and relapse specimens from individuals with KDM6A mutations showed an outgrowth of the KDM6A mutated tumor population at relapse. KDM6A-null myeloid leukemia cells were more resistant to treatment with the chemotherapeutic agents cytarabine (AraC) and daunorubicin. Inducible re-expression of KDM6A in KDM6A-null cell lines suppressed proliferation and sensitized cells again to AraC treatment. RNA expression analysis and functional studies revealed that resistance to AraC was conferred by downregulation of the nucleoside membrane transporter ENT1 (SLC29A1). Our results show that loss of KDM6A provides cells with a selective advantage during chemotherapy, which ultimately leads to the observed outgrowth of clones with KDM6A mutations or reduced KDM6A expression at relapse.

2019-06-18 | GSE128261 | GEO

Loss of DKM6A confers drug resistance in acute myeloid leukemia (ChIP-seq of AML cell lines MM-1 and MM-6)

2019-06-18 | GSE128259 | GEO

Expression analysis of Mll3 knockdown p53-/- HSPC vs. control p53-/- HSPC

2014-03-19 | GSE54313 | GEO

Systematic profiling of DNMT3A variants reveals protein instability mediated by the DCAF8 E3 ubiquitin ligase adaptor

Project description:Clonal hematopoiesis is a prevalent age-related condition associated with greatly increased risk of hematologic malignancies. Mutations in DNA methyltransferase 3A (DNMT3A) are the most common drivers of this state and contribute to multiple types of hematologic malignancy. DNMT3A variants occur across the gene and some are associated with particular disease states, but the functional relevance and mechanisms of pathogenesis of the majority of the mutations is unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, finding that 74% were loss-of-function mutations. Nearly half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and AML development. To identify the mechanisms underlying the instability, we conducted a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and therapeutic significance for patients with hematologic disease.

2021-06-24 | GSE178798 | GEO

Gene expression profiles associated with pediatric relapsed AML

2015-05-07 | GSE52891 | GEO

Genome-wide DNA methylation in MDS/secondary AML and de novo AML

Project description:An increasing body of work reveals aberrant hypermethylation of genes occurring in and potentially contributing to the pathogenesis of myeloid malignancies. Several of these diseases, such as myelodysplastic syndromes (MDS), are responsive to DNA methyltransferase inhibitors. In order to determine the extent of promoter hypermethylation in such tumors we compared the distribution of DNA methylation of 14,000 promoters in MDS and secondary AML patients enrolled in a phase I trial of 5-azacytidine and the histone deacetylase inhibitor entinostat against de novo AML patients and normal CD34+ bone marrow cells. The MDS and secondary AML patients displayed more extensive aberrant DNA methylation involving thousands of genes than did the normal CD34+ bone marrow cells or de novo AML blasts. Aberrant methylation in MDS and secondary AML tended to affect particular chromosomal regions, occurred more frequently in Alu poor genes, and included prominent involvement of genes involved in the WNT and MAPK signaling pathways. DNA methylation was also measured at days 15 and 29 after the first treatment cycle. DNA methylation was reversed at day 15 in a uniform manner throughout the genome, and this effect persisted through day 29, even without continuous administration of the study drugs. Keywords: DNA methylation profiling Direct comparison of DNA methylation in bone marrow samples from patients with Myelodysplastic syndrome or secondary Acute Myeloid Leukemia (AML) at baseline and after in vivo treatment with 5-azacytidine + etinostat. A comparison to de novo normal karyotype AML was also performed. Two control groups were included: one consisting of 8 CD34+ bone marrow samples from healthy donors and a second one consisting of matched CD34+ and CD34- fractions from the bone marrows of 4 healthy donors.

2010-05-15 | E-GEOD-17328 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data