Myeloproliferative Neoplasm (Mpn) Driver Mutations Are Enriched During Hematopoietic Stem Cell Differentiation In Patterns That Correlate With Clinical Phenotype And Treatment Response

Introduction. Philadelphia negative (Ph-neg) Myeloproliferative Neoplasms (MPNs) differ in clinical phenotype and outcomes despite harboring identical driver mutations. The biology behind phenotypic heterogeneity has been attributed to mutational burden, co-occurring mutations and mutation order, but remains uncertain. It is known that MPN mutations in JAK2, CALR, and MPL result in augmentation of cytokine signaling at different stages of hematopoietic differentiation towards myeloid lineages. Consistent with this, the JAK2V617F driver mutation is enriched in certain myeloid lineages compared to the hematopoietic stem and progenitor cell (HSPC) compartment (Anand et al. Blood 2011). We therefore hypothesized that the lineage-specific patterns of clonal enrichment that arise during hematopoietic differentiation from stem cells to mature progeny would account for phenotypic heterogeneity in MPNs.