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Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia
Jan Krönke1, Lars Bullinger, Veronica Teleanu
1Department of Internal Medicine III, Genomics Core Facility, University of Ulm, Ulm, Germany.
Abstract:
Mutations in the nucleophosmin 1 (NPM1) gene are considered 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 array profiling to detect copy number alterations (CNAs) and uniparental disomies (UPDs) 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 1 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.
Insights
Genomic complexity increases in relapsed acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations. Acquired aberrations and stable DNMT3A mutations offer insights into AML clonal evolution.
Area of Science:
- Hematology
- Genetics
- Cancer Biology
Background:
- Mutations in the nucleophosmin 1 (NPM1) gene are a key event in acute myeloid leukemia (AML) pathogenesis.
- Understanding clonal evolution in relapsed NPM1-mutated (NPM1mut) AML is crucial for treatment strategies.
Purpose of the Study:
- To investigate the role of clonal evolution in NPM1mut AML relapse.
- To identify genomic alterations acquired during relapse in NPM1mut AML.
Main Methods:
- Genome-wide single-nucleotide polymorphism array profiling to detect copy number alterations (CNAs) and uniparental disomies (UPDs).
- Comprehensive gene mutation screening in paired diagnostic and relapse bone marrow/peripheral blood samples from 53 NPM1mut AML patients.
Main Results:
- Genomic complexity significantly increased at relapse, with 55% of patients showing alterations compared to 25% at diagnosis.
- Recurrent acquired aberrations at relapse included deletions in tumor suppressor genes (e.g., ETV6, TP53, WT1) and homozygous FLT3 mutations via UPD13q.
- DNMT3A mutations demonstrated high stability (97%), and their persistence after NPM1mut loss suggested they may precede NPM1 mutations in AML pathogenesis.
Conclusions:
- Clonal evolution leads to increased genomic complexity in relapsed NPM1mut AML.
- Acquired genetic alterations at relapse provide potential therapeutic targets.
- Shared genetic aberrations between diagnosis and relapse samples indicate common ancestral clones, highlighting the importance of tracking clonal dynamics.
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