Mutations in JAK2, CALR, and MPL drive excessive myeloproliferation via constitutively active signaling downstream of JAK2. JAK2 associates with the cytoplasmic portion of a variety of receptors, such as those for erythropoietin (EPOR), thrombopoietin (MPL), and granulocyte/macrophage colony-stimulating factor (G-CSFR). JAK2 is also activated in response to additional cytokines (eg, growth hormone and IL-5) (not shown). (A) Mutant JAK2, shown in red, is constitutively active and leads to variable levels of erythroid, megakaryocytic, and, to a lesser degree, granulocytic proliferation and differentiation. It is unclear whether mutant JAK2 dimerizes with mutant or wild-type JAK2 with respect to the individual receptors. (B) Mutations in CALR and MPL result in aberrant activation of signaling downstream of the MPL receptor. Mutant CALR complexes with MPL in the ER. Both mutations in CALR and MPL result in receptor dimerization and activation of JAK2. MAPK/ERK, mitogen-activated protein kinases/extracellular signal-regulated kinases; PI3/AKT, phosphoinositide 3-kinase/serine/threonine kinase Akt; STAT, signal transducer and activator of transcription.