AML clonal phylogeny
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001001779 | EGA |
REPOSITORIES: EGA
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Project description:Acute myeloid leukemia (AML) is a hematological cancer that affects mainly the elderly. Although complete remission (CR) is achieved for the majority of the patients after induction and consolidation therapies, nearly two-thirds relapse within a short interval. Therefore, understanding of the biological factors that determine relapse has become a major interest in clinical AML. In order to identify the proteins and their phosphorylated modifications involved in AML relapse, we performed a global proteome and phosphoproteome study by liquid chromatography tandem mass spectrometry (LC-MS/MS) with primary cells from 41 AML patients at time of diagnosis that were defined as RELAPSE or REL_FREE according to their relapse status after a 5-year clinical follow-up post diagnosis. Our findings showed that the diagnostic sample of patients relapsing had increased levels of RNA processing and decreased expression of V-ATPases proteins along with CDKs and CSK2 activities. LC-MS/MS-based results were further validated with cell proliferation assays using V-ATPase inhibitor bafilomycin A1, CSK2 inhibitor CX-4945, CDK4/6 inhibitor abemaciclib and CDK2/7/9 inhibitor SNS-032. Our study presents molecules that could predict AML relapse and direct new therapeutic strategies that might circumvent more aggressive AML episodes.
2020-04-14 | PXD014997 | Pride
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
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.
2015-05-07 | GSE52891 | GEO
Project description:Genome-wide DNA methylation profiling of diagnosis, complete remission and disease relapse samples of an AML case with complex and unusual DNMT3A mutational profile. The Illumina Infinium MethylationEPIC BeadChip was used to obtain DNA methylation profiles across approximately 850,000 CpGs from bone marrow samples at the three different conditions of disease.
2022-05-10 | GSE202488 | GEO
Project description:Mutations in the nucleophosmin 1 (NPM1) gene are considered as a founder event in the pathogenesis of acute myeloid leukemia (AML). To address the role of clonal evolution in relapsed NPM1 mutated (NPM1mut) AML, we applied high-resolution genome-wide single-nucleotide polymorphism (SNP) array profiling to detect copy number alterations (CNA) and uniparental disomies (UPD) and performed comprehensive gene mutation screening in 53 paired bone marrow/peripheral blood samples obtained at diagnosis and relapse. At diagnosis, 15 aberrations (CNAs, n=10; UPDs, n=5) were identified in 13 patients (25%), whereas at relapse 56 genomic alterations (CNAs, n=46; UPDs, n=10) were detected in 29 patients (55%) indicating an increase in genomic complexity. Recurrent aberrations acquired at relapse included deletions affecting tumor suppressor genes [ETV6 (n=3), TP53 (n=2), NF1 (n=2), WT1 (n=3), FHIT (n=2)] and homozygous FLT3 mutations acquired via UPD13q (n=7). DNMT3A mutations (DNMT3Amut) showed the highest stability (97%). Persistence of DNMT3Amut in 5 patients who lost NPM1mut at relapse suggests that DNMT3Amut may precede NPM1mut in AML pathogenesis. Of note, all relapse samples shared at least one genetic aberration with the matched primary AML sample implying common ancestral clones. In conclusion, our study reveals novel insights into clonal evolution in NPM1mut AML. Bone marrow or peripheral blood samples from diagnosis, remission and relapse of 53 NPM1 mutated AML patient were analyzed on the Affymetrix Genome-Wide Human SNP 6.0 Array. Raw data (CEL-Files) were transformed to genotyping files (CHP) with Genotyping Console Version 4.2 from Affymetrix. Bioinformatic evaluation of CNAs was performed using dChipSNP and circular binary segmentation .
2013-05-30 | E-GEOD-46951 | biostudies-arrayexpress
Project description:Genome-wide analysis of single nucleotide polymorphisms in 64 acute myeloid leukemias has revealed that 20% exhibited large regions of homozygosity that could not be accounted for by visible chromosomal abnormalities in the karyotype. Further analysis confirmed that these patterns were due to partial uniparental disomy (UPD). Remission bone marrow was available from five patients showing UPD in their leukemias, and in all cases the homozygosity was found to be restricted to the leukemic clone. Two examples of UPD11p were shown to be of different parental origin as indicated by the methylation pattern of the H19 gene. Furthermore, a previously identified homozygous mutation in the CEBPA gene coincided with a large-scale UPD on chromosome 19. These cryptic chromosomal abnormalities, which seem to be nonrandom, have the characteristics of somatic recombination events and may define an important new subclass of leukemia. Patient No. from Table 1 of Raghavan et al 2005 and Sample name; Patient No: 1 = Sample name: AML sample 35 diagnosis; Patient No: 1 = Sample name: AML sample 107 remission; Patient No: 2 = Sample name: AML sample 37 diagnosis; Patient No: 3 = Sample name: AML sample 10 diagnosis; Patient No: 3 = Sample name: AML sample 44 remission; Patient No: 4 = Sample name: AML sample 20 diagnosis; Patient No: 5 = Sample name: AML sample 65 diagnosis; Patient No: 6 = Sample name: AML sample 69 diagnosis; Patient No: 6 = Sample name: AML sample 94 remission; Patient No: 7 = Sample name: AML sample 40 diagnosis; Patient No: 7 = Sample name: AML sample 41 remission; Patient No: 8 = Sample name: AML sample 64 diagnosis; Patient No: 9 = Sample name: AML sample 7 diagnosis; Patient No: 10 = Sample name: AML sample 49 diagnosis; Patient No: 10 = Sample name: AML sample 106 remission; Patient No: 11 = Sample name: AML sample 76 diagnosis; Patient No: 12 = Sample name: AML sample 79 diagnosis Experiment Overall Design: DNA from 64 diagnostic AML samples were analysed using Affymetrix 10K SNP arrays. Large regions of homozygosity were identified and compared with remission bone marrow where available.
2008-06-15 | E-GEOD-7490 | biostudies-arrayexpress
Project description:In the current study we will perform global metabolic profiling on serum samples obtained at diagnosis from pediatric AML patients (n=20) treated under St. Jude AML02 clinical trial to identify potential biomarkers of clinical significance. These patients include 10 responders and 10 non responders. In a subset of patients (n=7), we have matched samples that were obtained at remission allowing us to determine the change in serum metabolome at diagnosis and after remission followed by investigation of the metabolome change analysis with clinical response.
2015-08-27 | ST000270 | MetabolomicsWorkbench
Project description:Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To further characterize the genetic composition of NPM1 mutated (NPM1mut) AML, we assess mutation status of five recurrently mutated oncogenes (FLT3, DNMT3A, IDH1, IDH2, NRAS) in 129 paired NPM1mut samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1mut loss (n=11). To gain further insight into these NPM1mut loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1mut loss patients (pts) feature distinct mutational patterns that shared almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways including loss of characteristic NPM1mut associated gene expression patterns. In contrast, profiles of pts with persistent NPM1mut at relapse are reflected by a high overlap of mutations between diagnosis and relapse. Thus, our findings confirm that relapse often originates from persistent leukemic clones, though NPM1mut loss cases suggest a second “de novo” or treatment-associated AML (tAML) as alternative cause of “relapse" in a subgroup of cases.
2019-05-14 | GSE128602 | GEO
Project description:Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To further characterize the genetic composition of NPM1 mutated (NPM1mut) AML, we assess mutation status of five recurrently mutated oncogenes (FLT3, DNMT3A, IDH1, IDH2, NRAS) in 129 paired NPM1mut samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1mut loss (n=11). To gain further insight into these NPM1mut loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1mut loss patients (pts) feature distinct mutational patterns that shared almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways including loss of characteristic NPM1mut associated gene expression patterns. In contrast, profiles of pts with persistent NPM1mut at relapse are reflected by a high overlap of mutations between diagnosis and relapse. Thus, our findings confirm that relapse often originates from persistent leukemic clones, though NPM1mut loss cases suggest a second “de novo” or treatment-associated AML (tAML) as alternative cause of “relapse" in a subgroup of cases.
2019-05-14 | GSE128603 | GEO
Project description:The frequent occurrence of persistent or relapsed disease following induction chemotherapy in AML necessitates a better understanding of the clonal relationship of AML in various disease phases. In this study, we employed SNP 6.0 array-based genomic profiling of acquired copy number aberrations (aCNA) and copy neutral LOH (cnLOH) together with sequence analysis of recurrently mutated genes to characterize paired AML genomes. We analyzed 28 AML sample pairs from patients that achieved complete remission with chemotherapy and subsequently relapsed and 11 sample pairs from patients with persistent disease following induction chemotherapy. Through review of aCNA/cnLOH and gene mutation profiles in informative cases we demonstrate that relapsed AML invariably represents reemergence or evolution of a founder clone. Furthermore, all individual aCNA or cnLOH detected at presentation persisted at relapse indicating that this lesion type is proximally involved in AML evolution. Analysis of informative paired persistent AML disease samples uncovered cases with two coexisting dominant clones of which at least one was chemotherapy sensitive and one resistant, respectively. These data support the conclusion that incomplete eradication of AML founder clones rather than stochastic emergence of fully unrelated novel clones underlies AML relapse and persistence with direct implications for clinical AML research This study is based on 39 patients with AML for which either paired enrollment or relapse samples or persistent disease samples were available. The patients were enrolled into this study at the University of Michigan Comprehensive Cancer Center. The study was approved by the University of Michigan Institutional Review Board (IRBMED #2004-1022) and written informed consent was obtained from all patients prior to enrollment. Genomic DNA was extracted from purified AML blasts and paired buccal cells. DNA thus obtained was hybridized to Affymetrix SNP 6.0 arrays. Note: There is no normal sample available for MIAML015.
2013-02-12 | E-GEOD-41646 | biostudies-arrayexpress