Clonal evolution patterns in acute myeloid leukemia with NPM1 mutation

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Abstract Mutations in thenucleophosmin 1(NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition ofNPM1mutated (NPM1mut) AML, we assess mutation status of five recurrently mutated oncogenes in 129 pairedNPM1mutsamples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse includingNPM1mutloss (n = 11). To better understand theseNPM1mutloss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse,NPM1mutloss 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 persistentNPM1mutare reflected by a high overlap of mutations between diagnosis and relapse. Our findings confirm that relapse often originates from persistent leukemic clones, thoughNPM1mutloss cases suggest a second “de novo” or treatment-associated AML (tAML) as alternative cause of relapse.

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