Model depicting the effects of mutant JAK2 and IFN-α on the proportion of megakaryocyte-biased (CD41^hi) HSCs. (A) HSC homeostasis in BM of WT mice. The proportion of CD41^hi HSCs is low (∼30%). (B) HSC pool in MPN mice expressing mutant JAK2. The proportion of CD41^hi HSCs is increased (≤50%) because of the expression of mutant JAK2. CD41^hi HSCs in mice are characterized by lower Epcr expression, active cell cycle state, increased cell size, increased ROS levels, reduced long-term reconstitution potential in vivo, and Mk-biased potential in vitro. The effect of the mutant JAK2 on CD41 subset is mediated by the VF-induced IFN response and requires the presence of Ifnr1. (C) Summary of alterations in the HSC compartment of mice or patients with MPN treated with pegIFNα.