Analysis of JAK2 VAFs in hematopoietic progenitors. (A) Analysis of single colonies grown in methylcellulose. Single erythroid colonies (burst-forming unit–erythroid [BFU-E]) and granulocyte or granulocyte/monocyte colonies (colony-forming unit granulocyte/granulocyte-macrophage [CFU-G/GM]) were picked, and the percentage of JAK2-mutant colonies was converted into VAF by taking into account the heterozygous and homozygous state of each colony. (B) JAK2 VAF in FACS-sorted progenitor cells and mature blood cells. Data from 17 MPN patients are shown. Data points connected by solid lines were obtained from FACS-sorted progenitor cells. Dashed lines connect the progenitors with their corresponding mature cells isolated from peripheral blood. (C) Model depicting the stages of hematopoiesis in which the clonal expansion occurred in MPN patients with low JAK2 VAF. (D) Schematic illustration of dynamics in a branched population structure. (E) Modeling of a common platelet and red cell–biased pattern using the branched compartmental model of hematopoiesis. The distribution of JAK2-mutant cells observed in MPN patients with low VAF can be reproduced by altering the division rate (b), self-renewal (a), and death (d) probabilities, and the differentiation bias (c) at specific stages of hematopoietic development. For the clonal expansion during terminal stages of megakaryopoiesis, Δa signifies the probability that megakaryocytes repeatedly undergo endomitosis resulting in higher ploidy, and the division rate Δb stands for the number of endomitoses per time unit, for example, per day. Hematopoietic cell compartments are indicated on the x-axis. **P < .01; ****P < .0001. CLP, common lymphoid progenitor; CMP, common myeloid progenitor; EP, erythroid progenitor; HSPC, hematopoietic stem and progenitor cell; Meg, megakaryocyte; MEP, megakaryocyte-erythroid progenitor.