Evolution of MPNs originating from a single HSC that acquired a disease driver mutation. Model summarizing the events from the acquisition of JAK2-p.V617F until the development of MPN disease. The early events occur inside the bone marrow. A single HSC with JAK2-p.V617F can divide to yield 2 HSC daughter cells that carry the mutation, which leads to persistence, and later limited expansion of the mutated HSCs. Alternatively, the mutated HSC can differentiate into committed progenitors that produce a wave of mutant hematopoietic cells, but eventually are exhausted, due to loss of stemness. The mutant HSCs can also be eliminated at this early stage by cells of the immune system. During this phase, cells carrying JAK2-p.V617F are not yet detectable in peripheral blood (“pre-CHIP phase”). After expansion of the mutated HSCs and with a latency of years or decades, mature hematopoietic cells carrying JAK2-p.V617F are produced that become detectable in peripheral blood as “clonal hematopoiesis of undetermined potential (CHIP).” In only a minority of cases, the JAK2-p.V617F mutant HSC clone expands and produces committed progenitors that become dominant in bone marrow and can be diagnosed as MPN with elevated blood counts in peripheral blood. The factors favoring this conversion from CHIP to MPN are listed under the red arrow. The size of the JAK2-p.V617F mutant HSC clone can be reduced by interferon-α (IFNα), which acts by pushing the mutant HSCs into the cell cycle and thereby exhausting them,