Similar Datasets
Project description:Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition of NPM1 mutated (NPM1mut) AML, we assess mutation status of five recurrently mutated oncogenes 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 better understand 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 share almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways. In contrast, profiles of pts with persistent NPM1mut are reflected by a high overlap of mutations between diagnosis and relapse. 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.
| S-EPMC6497712 | biostudies-literature
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: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:Clonal evolution patterns in acute myeloid leukemia with NPM1 mutation
| PRJNA528267 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2017-05-03 | E-GEOD-68469 | biostudies-arrayexpress
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: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.
2013-05-30 | GSE46951 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-05-03 | GSE68469 | GEO
Project description:SETD2 is the only methyltransferase for H3K36me3, and our previous study has firstly demonstrated that it functioned as one tumor suppressor in hematopoiesis. Consistent with it, SETD2 mutation, which led to its loss of function, was identified in AML. However, the distribution and function of SETD2 mutation in AML remained largely unknown. Herein, we integrated SETD2-mutated AML cases from our center and literature reports, and found that NPM1 mutation was the most common concomitant genetic alteration with SETD2 mutation in AML, with its frequency even higher than MLL rearrangement and AML1-ETO. Though this result indicated the cooperation of SETD2 and NPM1 mutations in leukemogenesis, our functional study showed that SETD2 was required for the proliferation of NPM1-mutated AML cell line OCI-AML3, but not MLL-rearranged AML cell line THP-1, via maintaining its direct target NPM1 expression, which was just opposite to its role of tumor suppressor. Therefore, we speculated that SETD2 possibly had two different faces in distinct subtypes and stages of AML.
| S-EPMC7659109 | biostudies-literature
Project description:Nucleophosmin (NPM1) is a widely expressed nucleocytoplasmic shuttling protein with prominent nucleolar localization. It is estimated that 25-35% of adult patients with acute myeloid leukemia (AML) carry NPM1 mutations. The classic NPM1 type A mutation occurs in exon 12, which accounts for 75-80% of adult patients with NPM1-mutated AML. It produces an additional leucine and valine-rich nuclear export signal (NES) at the C-terminus, and causes aberrant cytoplasmic dislocation of NPM1 protein. Notably, emerging evidence indicates that besides the classic type A mutation, rare mutants occurring in other exons may also lead to the imbalance of the nucleocytoplasmic shuttle of NPM1. Identification of novel non-type A mutants is crucial for the diagnosis, prognosis, risk stratification and disease monitoring of potential target populations. Here we reported a novel NPM1 mutation in exon 5 identified from a de novo AML patient. Similar to the classic type A mutation, the exon 5 mutation had the NPM1 mutant bound to exportin-1 and directed the mutant into the cytoplasm by generating an additional NES sequence, resulting in aberrant cytoplasmic dislocation of NPM1 protein, which could be reversed by exportin-1 inhibitor leptomycin B. Our findings strongly support that besides the exon 12 mutation, the exon 5 mutant is another NPM1 "born to be exported" mutant critical for leukemogenesis. Therefore, similar to the classic type A mutation, the identification of our novel NPM1 mutation is beneficial for clinical laboratory diagnosis, genetic risk assessment and MRD monitoring.
| S-EPMC10548603 | biostudies-literature