Figure 2.

Order of mutation acquisition influences the evolution of disease. This model depicts the manner in which single hematopoietic units (left), consisting of stem cells, progenitors, and differentiated cells, acquire mutations over time. Some units are hyperproliferative and produce excess differentiated cells that contribute to the disease phenotype. The numbers represent the acquisition of the first mutation (1), second mutation (2), and JAK2 V617F homozygosity (3). Patients who acquire a TET2 mutation first gain a self-renewal advantage but do not overproduce downstream progeny. The expansion of the TET2-alone clone (bold borders) without excess differentiated cells leads to clonal expansion without immediate clinical presentation. Hematopoietic stem cells that acquire a secondary JAK2 mutation (pink fill) compete with the TET2-alone clone, and their increased proliferation at the progenitor level drives an overproduction of terminal cells. When homozygosity is acquired as a third event (red fill), this clone has limited space to expand because of the high self-renewal activity of TET2-alone and TET2–JAK2–heterozygous clones. Patients who acquire a JAK2 mutation first (pink fill, lower panel) produce excess differentiated cells in the absence of a distinct self-renewal advantage in the hematopoietic stem cells. When a secondary TET2 mutation is acquired, hematopoietic stem cells obtain a self-renewal advantage and JAK2–TET2–mutant cells expand at the stem-cell level. Hematopoietic stem cells with loss of heterozygosity of JAK2 V617F (acquired before or after the TET2 mutation) (red fill) also have space to expand and result in a more pronounced excess of differentiated cells. This excess production would explain both the presentation as a polycythemia vera and the elevated risk of thrombotic events in JAK2-first patients. Figure and legend reprinted with permission from NEJM.