Disease heterogeneity following acquisition of the JAK2V617F mutation in a single HSC. X-axis represents time following acquisition of JAK2V617F indicated by the arrow. Y-axis represents relative contribution from this HSC clone to each lineage, indicated by color. (A) JAK2V617F occurs in a platelet-biased HSC resulting in ET. (B) JAK2V617F occurs in a lineage-balanced HSC resulting in PV with trilineage myeloproliferation. (C) JAK2V617F occurs in an HSC with limited self-renewal capability resulting in CHIP. (D) JAK2V617F precedes acquisition of a TET2 mutation resulting in a PV phenotype. (E) TET2 precedes acquisition of a JAK2V617F mutation resulting in an ET phenotype. (A-C) represent hypotheses to explain how HSC heterogeneity may influence MPN phenotype. (D-E) represent an interpretation of published data demonstrating that the order in which JAK2V617F and TET2 mutations are acquired influences MPN phenotype.