GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE296nnn/GSE296381/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE296381GEOGSEfalseClonal evolution permits outgrowth of chemoresistant LMPP-like early progenitors in relapsed NPM1c AMLThe most recurrent acute myeloid leukemia (AML) driver in adult patients is a DNA frameshift insertion in the Nucleophosmin 1 (NPM1) gene. This mutation causes a translocation of the coding protein from the nucleus to the cytoplasm (NPM1c). We have generated paired single-cell multi-omics profiles for ~205,000 bone marrow cells collected from NPM1c AML patients at diagnosis and relapse. Detailed single-cell clonal analysis unveiled the evolution, expansion, and concomitant phenotypic changes of pathogenic AML (sub)clones. Blasts with an internal tandem duplication in the FLT3 gene (FLT3-ITD+ blasts) were often lowly abundant at diagnosis but expanded drastically at relapse at the expense of other blasts. Intriguingly, genetically identical FLT3-ITD+ blasts switched from granulocyte-monocyte progenitor-like at diagnosis toward more immature lympho-myeloid primed progenitor (LMPP)-like blasts at relapse. Our data shows that clonal evolution and the accumulation of a FLT3-ITD, is a key evolutionary event that alters AML blast plasticity with minimal changes in the blast phenotype. Increased plasticity favors the specific selection and expansion of FLT3-ITD+ blasts, which adopt a unique LMPP-like phenotype. The overriding transition between diagnosis and relapse suggests that therapeutic interventions (against proliferating cells) could license or accelerate this shift, highlighting the need for a tailored drug composition to target relapsed NPM1c AML.2026/05/01GSE296381GSM8969439GSM8969428GSM8969438GSM8969427GSM8969429GSM8969435GSM8969445GSM8969434GSM8969437GSM8969426GSM8969436GSM8969442GSM8969431GSM8969441GSM8969430GSM8969444GSM8969433GSM8969432GSM8969443GSM896944024676296381Homo sapiens