Gain-of-function and loss-of-function mutations associated with aberrant STAT activation. Adult and pediatric myeloproliferative disorders are characterized by dysregulated balance between activation and inactivation of the JAK-STAT pathway. Mutant kinase activation can occur from BCR-ABL translocation or in Philadelphia chromosome–negative patients from a short list of mutations in receptor and intracellular signaling components. Loss of negative regulator function such as Lnk, as described by Oh and colleagues,¹  also facilitates JAK-STAT activation. This convergence of signaling suggests that JAK-STAT components may be good therapeutic targets for this broad class of disorders. Professional illustration by Paulette Dennis.