Clonal evolution permits outgrowth of chemoresistant LMPP-like early progenitors in relapsed NPM1c AML

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.