Here we show that blocking TNFR2 but not TNFR1 selectively inhibits MPN cells over normal controls and implicate X-linked inhibitor of apoptosis (XIAP), cIAP and mitogen-activated protein kinase 8 (MAPK8) as key mediators of differential responses to TNF. Here, MAP3K8 is linked to myeloproliferative neoplasm.