Clonal Metamorphosis: Deconstructing MPN Evolution with Single-Cell and Spatial Multi-Omics.

Myeloproliferative neoplasms (MPNs) present a fundamental paradox: despite sharing a small set of canonical driver mutations in JAK2, CALR, or MPL, patients exhibit striking heterogeneity in disease latency, clinical presentation, and evolutionary trajectories to myelofibrosis or secondary acute myeloid leukemia. This review synthesizes recent advances in single-cell and spatial multi-omic technologies that are resolving this paradox by moving analysis from bulk averages to individual cells and their microenvironmental ecosystems. We examine how targeted single-cell DNA sequencing reconstructs clonal architectures and phylogenies, revealing that driver mutations arise within complex mosaics where mutation order, co-mutation context, and cellular ancestry determine phenotypic outcomes. Integrated single-cell transcriptomic and epigenomic profiling exposes within-clone heterogeneity, lineage biases, and functional states that explain variable penetrance and therapy responses. Spatial transcriptomics, especially when integrated with single-cell transcriptomics, histopathology, and multiplex proteomics, further demonstrates that malignant hematopoietic stem and progenitor cells actively remodel bone marrow niches, creating localized inflammatory and fibrotic microenvironments that select for aggressive subclones. Together, these approaches support a new ecological model of MPN pathogenesis in which early epigenetic hits create permissive stem cell reservoirs, clonal competition and cooperation shape disease progression, and non-cell-autonomous niche and immune signals drive malignant metamorphosis. We discuss how this framework refines prognostication, informs rational combination therapies targeting both malignant cells and their ecosystem, and enables real-time monitoring of clonal dynamics, ultimately charting a course from descriptive atlases to actionable clinical strategies.