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Clonal evolution in relapsed NPM1 mutated acute myeloid leukemia

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46951 | GEO | 2013/05/30

SECONDARY ACCESSION(S): PRJNA203255

REPOSITORIES: GEO

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Clonal evolution in relapsed NPM1 mutated acute myeloid leukemia

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 .

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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.

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DNMT3A R882 mutations promote anthacyline resistance through impaired DNA-damage sensing [Bisulfite-Seq]

Project description:Although the majority of acute myeloid leukemia (AML) patients initially respond to chemotherapy, most of them subsequently relapse due to persistent, chemoresistant disease. However, the mechanistic basis by which AML cells persist during chemotherapy has not been fully delineated. Recurrent somatic mutations in the DNA methyltransferase 3A gene (DNMT3A), most frequently at arginine 882 (DNMT3Amut), are commonly observed in AML patients, and are also detected in elderly subjects with clonal hematopoiesis in the absence of leukemic transformation. DNMT3Amut AML patients have an inferior outcome when treated with standard dose daunorubicin-based induction chemotherapy, suggesting that DNMT3Amut AML cells can persist following chemotherapy and drive relapse. DNMT3Amut cells show impaired nucleosome eviction and chromatin remodeling in response to DNA damage in the setting of anthracycline exposure. This defect leads to an inability to sense and repair DNA damage, which results in the accumulation of single-stranded DNA breaks and increased mutagenesis. Our studies identify a critical role for DNMT3A R882 mutations in driving AML chemoresistance, and highlight the importance of chromatin remodeling in the response to cytotoxic chemotherapy.

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Project description:In this work we dissect the functional role of the HOXB-AS3 long non coding RNA in patients with NPM1-mutated (NPM1mut) acute myeloid leukemia (AML). We show that HOXB-AS3 regulates the proliferative capacity of NPM1mut AML blasts in vitro and in vivo. HOXB-AS3 was found to interact with the ErbB3-binding protein 1 (EBP1) and guide EBP1 to the ribosomal DNA locus. Via this mechanism HOXB-AS3 regulates ribosomal RNA transcription and de novo protein synthesis. We propose that in the context of NPM1 mutations, HOXB-AS3 overexpression acts as a compensatory mechanism, which allows adequate protein production in leukemic blasts.

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Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia

Project description:Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known how mutant NPM1 (NPM1mut) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1mut AML. Using a CRISPR-Cas9 genome editing domain screen, we show NPM1mut AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacological small-molecule inhibition of the menin-MLL protein interaction had profound anti-leukemic activity in human and murine models of NPM1mut AML in vitro and in vivo. Combined pharmacological inhibition of menin-MLL and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1mut leukemia. Together, MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1 and FLT3 expression and are therapeutic targets in NPM1mut AML. Combinatorial small-molecule inhibition has synergistic on target activity and constitutes a novel therapeutic concept for this common AML subtype. RNA sequencing data of the human AML cell lines OCI-AML2 and OCI-AML3 comparing EPZ004777 [10ÂµM] drug treatment versus DMSO vehicle control; experiments performed in biological triplicates.

2016-08-22 | E-GEOD-85107 | biostudies-arrayexpress

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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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