Effects of Dnmt3a deletion on the proliferation, self-renewal, differentiation, and fitness of long-term HSCs carrying JAK2V617F in the absence and presence of treatment with IFN-α. Compared with wild-type JAK2 HSCs, JAK2V617F HSCs exhibit higher cycling, higher proliferation, lower self-renewal, and increased differentiation. After IFN-α treatment, JAK2V617F HSCs increase their cell cycling, with a higher proliferation leading to both a further decrease in self-renewal capacity and an increase in differentiation and probably of apoptosis. This increased proliferation is associated with a replicative stress, including a higher level of reactive oxygen species (ROS) and DNA damage. In contrast, the Dnmt3a^–/–JAK2V617F HSCs, although exhibiting a similar cell cycling, exhibit proliferation oriented toward self-renewal at the expense of differentiation, which is not modified by IFN-α.