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Clonal evolution patterns in acute myeloid leukemia with NPM1 mutation

Sibylle Cocciardi¹, Anna Dolnik¹, Silke Kapp-Schwoerer¹

¹Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany.

Nature Communications

|May 4, 2019

Abstract:

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 (NPM1^mut) AML, we assess mutation status of five recurrently mutated oncogenes in 129 paired NPM1^mut samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1^mut loss (n = 11). To better understand these NPM1^mut loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1^mut 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 NPM1^mut are reflected by a high overlap of mutations between diagnosis and relapse. Our findings confirm that relapse often originates from persistent leukemic clones, though NPM1^mut loss cases suggest a second "de novo" or treatment-associated AML (tAML) as alternative cause of relapse.

Insights

Genetic analysis of acute myeloid leukemia (AML) reveals that while most relapses stem from persistent clones, some NPM1-mutated AML cases involve NPM1 loss, suggesting new or treatment-associated AML origins.

Area of Science:

Hematology
Cancer Genetics
Molecular Oncology

Background:

Mutations in the nucleophosmin 1 (NPM1) gene are key drivers in acute myeloid leukemia (AML) pathogenesis.
Understanding genetic evolution from diagnosis to relapse is crucial for AML treatment strategies.

Purpose of the Study:

To investigate the genetic landscape of NPM1-mutated (NPM1^mut) AML at diagnosis and relapse.
To characterize the distinct genetic profiles of NPM1^mut loss cases at relapse.

Main Methods:

Analysis of mutation status for five recurrently mutated oncogenes in 129 paired NPM1^mut AML samples.
Whole exome sequencing (WES) and RNA-Seq performed on NPM1^mut loss samples at relapse.

Main Results:

A significant genetic shift was observed between diagnosis and relapse in NPM1^mut AML, including 11 cases with NPM1^mut loss.
NPM1^mut loss patients at relapse exhibited unique mutational patterns with minimal overlap with diagnosis samples, affecting different signaling pathways.
Patients with persistent NPM1^mut showed high mutation overlap between diagnosis and relapse.

Conclusions:

Relapse in NPM1^mut AML typically arises from persistent leukemic clones.
NPM1^mut loss at relapse suggests alternative etiologies, including de novo or treatment-associated AML (tAML).

Read full analysis

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