Putative model of evolution from PV toward post-PV myelofibrosis, through modification of the HSC compartment. The left diagram shows a model of hematopoiesis from the HSCs to mature cells in PV. JAK2V617F cells are in gray, and JAK2WT cells in white. The properties of JAK2V617F HSCs are not modified, compared with JAK2 WT HSC, either in term of self-renewal or proliferation. However, a major amplification of terminal myeloid differentiation is observed, from the stage of differentiation when progenitors express homodimeric type I cytokine receptors. We hypothesize that JAK2V617F cells would produce TGF-β1, responsible for the progressive development of myelofibrosis, and another cytokine or chemokine (X-factor) responsible for the progressive destruction of normal hematopoiesis, that could also be TGF-β1. As JAK2WT HSCs would express the receptors of X-factor, they would be sensitive to X-factor–negative regulatory signals and therefore progressively destructed. On the contrary, JAK2V617F HSCs would have a decreased expression of X-factor receptor or signaling and would express antiapoptotic proteins, such as bcl-xl, being therefore insensitive to apoptosis. The right panel shows the stage of post-PV myelofibrosis, when the increasing and persistent production of TGF-β1 would induce myelofibrosis and when JAK2WT HSCs have been destructed following X-factor stimulation. The only remaining HSCs are thus JAK2V617F, without any increase in self-renewing properties.