JAK2 mutants (e.g., JAK2V617F) and their importance as drug targets in myeloproliferative neoplasms

Abstract

The Janus kinase 2 (JAK2) mutant V617F and other JAK mutants are found in patients with myeloproliferative neoplasms and leukemias. Due to their involvement in neoplasia and inflammatory disorders, Janus kinases are promising targets for kinase inhibitor therapy. Several small-molecule compounds are evaluated in clinical trials for myelofibrosis, and ruxolitinib (INCB018424, Jakafi®) was the first Janus kinase inhibitor to receive clinical approval. In this review we provide an overview of JAK2V617F signaling and its inhibition by small-molecule kinase inhibitors. In addition, myeloproliferative neoplasms are discussed regarding the role of JAK2V617F and other mutant proteins of possible relevance. We further give an overview about treatment options with special emphasis on possible combination therapies.

Keywords: JAK2V617F; essential thrombocythemia; myeloproliferative neoplasms; polycythemia vera; primary myelofibrosis.

Figure 1. Conformational and phosphorylation events leading to JAK activation. IL2 signaling is used as an example. For clarity only the signal transducing receptor chains (IL2Rβ [β] and IL2Rγ [γ]) are shown. The scheme on the left shows the inactive state of a receptor/JAK complex. The binding of the cytokine (1a) impinges conformational changes in the receptor complex. JAKs are sensitive to these changes since they bind to the membrane-proximal region of cytokine receptors. This results in a conformational, phosphorylation-independent activation of the two JAKs (1b). Activation of downstream signaling is already promoted at this stage (2), although at a non-maximal level. The now activated JAKs phosphorylate each other “in trans” (3a and 3b). This leads to a full-fledged activation of the JAKs and maximal downstream signaling (4) (here: STAT5 phosphorylation). The different steps of the activation process are derived from a study using kinase-inactive, constitutively active and analog-sensitive mutants of JAK1 and JAK3 in the context of IL2 signaling.

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. 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.

Figure 3. Proportion of patients with PV, ET, or PMF carrying different genetic abnormalities related to JAK-STAT signaling.