An evolutionary pathway to MPN-BP. After the acquisition of a JAK2 V617F or similar driver mutation by a hematopoietic stem cell (depicted in yellow), host genetic, epigenetic, and microenvironmental factors can facilitate the emergence of asymptomatic clonal hematopoiesis (depicted in green), subsequent clonal expansion, and emergence of an MPN phenotype (depicted as doublet of green cells). The acquisition of additional mutations, including high-risk mutations (ASXL1, IDH1/2, SRSF2, EZH2, TP53), may lead to clonal evolution and disease progression and may ultimately culminate in MPN-BP (depicted as an outgrowth/cluster of red cells).