Reconstructing the Lineage Histories and Differentiation Trajectories of Individual Cancer Cells in Myeloproliferative Neoplasms

Some cancers originate from a single mutation event in a single cell. Blood cancers known as myeloproliferative neoplasms (MPNs) are thought to originate when a driver mutation is acquired by a hematopoietic stem cell (HSC). However, when the mutation first occurs in individuals and how it affects the behavior of HSCs in their native context is not known. Here we quantified the effect of the JAK2-V617F mutation on the self-renewal and differentiation dynamics of HSCs in treatment-naive individuals with MPNs and reconstructed lineage histories of individual HSCs using somatic mutation patterns. We found that JAK2-V617F mutations occurred in a single HSC several decades before MPN diagnosis—at age 9 ± 2 years in a 34-year-old individual and at age 19 ± 3 years in a 63-year-old individual—and found that mutant HSCs have a selective advantage in both individuals. These results highlight the potential of harnessing somatic mutations to reconstruct cancer lineages. [Display omitted] •Single-cell transcriptome and whole-genome sequencing of HSPCs from individuals with MPNs•The JAK2-V617F mutation occurs in a single HSC decades before diagnosis•JAK2-V617F HSCs have increased fitness in native human hematopoiesis•JAK2 mutant fraction varies in myeloid progenitor compartments in the same individuals Van Egeren et al. investigated the effect of the JAK2-V617F mutation in individuals with myeloproliferative neoplasms (MPNs) using single-cell profiling and found that the mutation occurs decades before MPN diagnosis and increases the fitness of HSCs. JAK2-V617F induces a megakaryocyte-erythroid differentiation bias. The JAK2-mutant fraction varies in myeloid compartments in the same individuals.