Canonical and noncanonical actions of JAK2 and opportunities for therapeutic targeting. JAK2 transduces cytokine and growth factor signals from membrane-bound receptors through phosphorylation of the STAT family of transcription factors. Negative regulators of JAK2, such as LNK, CBL, and SOCS, lead to ubiquitinylation and proteasomal degradation of JAK2, whereas protein tyrosine phosphatases (PTPs) dephosphorylate cytokine receptors, JAKs, and STATs. The protein inhibitor of STATs (PIAS) prevents the binding of STATs to target DNA. JAK2 is a client of the chaperone protein HSP90, and HSP90 inhibitors and HDAC6 inhibitors (through acetylation and disruption of HSP90 function) promote degradation of JAK2. JAK2 signals downstream to the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling cascades, which provides opportunities for combined inhibition of JAK2 and PI3K, mTOR, or MEK1/2. BH3 mimetics promote mitochondrial apoptosis, and synergism with ruxolitinib in MPN cells and animal models has been shown. Synergism between ruxolitinib and the selective inhibitor of nuclear export selinexor has also been demonstrated preclinically. Activated JAK2 promotes cell cycle progression through several mechanisms discussed in the text, making combined inhibition of JAK2 and CDK4/6 a rational approach. Finally, nuclear JAK2 phosphorylates PRMT5 and histone H3, activating transcription of many genes, including those encoding the PIM kinases, Bcl-xL, D-type cyclins, the cell cycle phosphatase CDC25A, and SOCS (negative feedback). Epigenetic deregulation is frequent in MPNs, and combinations of ruxolitinib with epigenetic modifiers such as azacitidine and panobinostat have shown promise in the clinic. Combinations of ruxolitinib with immunomodulatory drugs are also being pursued. Adapted, with permission, from Meyer and Levine.¹⁶⁰