Figure 2. Schematic representation of pathways related to signaling of JAK2V617F and regulation of its expression levels. A number of possible pharmacological approaches have been described that target proteins in the scheme (e.g., mTOR, MEK, HSP90, Aurora A/B, …). Other kinases involved in these pathways (e.g., PI3K, Akt, Pim, Erk1/2, …) might also be promising targets for combination treatments. In addition to Aurora kinases, further kinases influencing cell cycle progression also represent interesting targets (cyclin-dependent kinases [Cdk] and polo-like kinases [Plk]). Inhibition of the Bcl-2 family members might counteract anti-apoptosis. Interference with JAK expression levels has been shown to suppress JAK-STAT signaling either by inhibiting chaperone functions (HSP90) or by using deubiquitinase inhibitors.²¹⁶ Future approaches could also involve the targeting of adaptor proteins such as GAB1/2 which orchestrate the activation of the different signaling pathways in the signalosome at the receptor.