Mechanism of action of the different types of oncogenic mutations in myeloid diseases: “initial mutations” may precede “driver mutations,” which are disease initiating. In MPN, JAK2^V617F, CALR, and MPL mutations are recognized as “drivers.” During disease course, additional mutations are incurred; some of these may constitute “high-risk mutations,” for example, ASXL1, EZH2, SRSF2, and IDH1/2, which promote leukemic transformation. Marcault and colleagues describe a novel type of mutation, “sentinel mutations,” the acquisition of which drastically increases the likelihood of leukemic transformation, even though in some patients the mutation does not occur in the cells that form the leukemic clone. The authors suggest that paracrine mechanisms may contribute to leukemic transformation in patients with MPN. It appears that mutations in the same genes, for example, NFE2, can act either as “sentinels” or as “high-risk mutations.” HSCs, hematopoietic stem cells.