GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE296nnn/GSE296649/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE296649GEOGSEfalseClonal evolution permits outgrowth of chemoresistant LMPP-like early progenitors in relapsed NPM1c AML [scRNA-Seq]The 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.2026/05/01GSE296649GSM8974228GSM8974227GSM8974229GSM8974220GSM8974222GSM8974221GSM8974224GSM8974223GSM8974226GSM8974225GSM8974196GSM8974195GSM8974239GSM8974238GSM8974198GSM8974231GSM8974230GSM8974197GSM8974233GSM8974232GSM8974199GSM8974235GSM8974234GSM8974237GSM8974236GSM8974240GSM8974206GSM8974205GSM8974249GSM8974208GSM8974207GSM8974209GSM8974242GSM8974241GSM8974244GSM8974200GSM8974243GSM8974202GSM8974246GSM8974201GSM8974245GSM8974204GSM8974248GSM8974247GSM8974203GSM8974251GSM8974250GSM8974217GSM8974216GSM8974219GSM8974218GSM8974252GSM8974211GSM8974210GSM8974213GSM8974212GSM8974215GSM89742141857324676296649Homo sapiens