A working model describing how hTpoR responds to different activating cues and transmits downstream signaling via overlapping but distinct conformations. The active orientations and dimeric interfaces of hTpoR induced by Tpo and oncogenic JAK2V617F are strikingly distinct with a clockwise rotation of 110° from Tpo- to JAK2V617F-induced conformation. Amino acid Q516 of hTpoR is critical for JAK2V617F-induced activation with negligible effect on that induced by Tpo. Thus, targeting JAK2V617F-specific active conformation serves as a proof-of-principle strategy to develop new drugs for the treatment of JAK2V617F+ MPN.