Secondary site mutations restoring physiologic function for JAK2 V617F and identification of novel allosteric sites in oncoproteins: new therapeutic opportunities for blood malignancies

Myeloproliferative neoplasms (MPN) are hematological disorders resulting in the overproduction of erythroid, megakaryocytic or granulocytic cells. The oncoprotein JAK2 V617F has been recognized as the most common molecular event associated with MPNs. The mutation V617F lies in the pseudokinase domain and activates the adjacent kinase domain by a process which is not yet clear. Understanding the mechanism by which V617F activates JAK2 is a key challenge for the field of MPNs. Indeed, elucidating the mechanism of constitutive activation at the molecular level could guide future drug design towards more specific inhibitory strategies. We aimed to determine the mechanism of activation of JAK2 V617F. We identified regulatory sites around the JH2 αC and the SH2-JH2 linker that are specific to controlling the activity of the oncoprotein. We showed that by modulating these allosteric sites, we could restore wild-type phenotype to JAK2 and normal response to cytokine stimulation. These new allosteric sites provide opportunities for the identification of a new class of pharmaceuticals that could have improved specificity and potency toward JAK2 V617F.