Dysregulated JAK2 is at the apex of three classic oncogenic signaling cascades including STAT, PI3K/Akt/mTOR, and MAPK pathways. Their interrelationship and dependencies downstream of JAK2 in MPN cells is incompletely understood. Combined pathway inhibition in vitro might prove beneficial due to a synergistic impact on functionally redundant oncogenic axes, might allow lower doses of the different agents with better tolerability, and might avoid or delay the development of resistance.