Heterogeneity in the MPN stem and progenitor cell compartments. (A) Proposed model of factors affecting JAK-STAT signaling mutation acquisition in the MPN cell-of-origin (HSC) that may influence the disease phenotype/risk of evolution. The timing of mutation acquisition can be as early as fetal origin to adult onset and may affect disease evolution. (B) Mutation acquisition in a lineage-biased HSC may influence the disease phenotype; a mutation arising in a PLT-biased HSC leading to an ET phenotype, whereas in a balanced/myeloid-biased HSC may lead to a PV/MF phenotype. (C) Intrapatient single-cell multiomic analysis of mutant and nonmutant HSPC by applying methodologies (TARGET-seq,^57,58 GoT⁵⁹) to detect mutation information (genomic DNA) and gene expression (messenger RNA) to uncover mutant-specific gene signatures and potential therapeutic targets. ET, essential thrombocythemia; HSPCs, hematopoietic stem and progenitor cells; HSC, hematopoietic stem cell; MK, megakaryocyte; PLT, platelet; PV, polycythemia vera; MF, myelofibrosis.