Figure 1.

The phenotypic driver mutations of myeloproliferative neoplasms (MPNs) act through JAK-STAT signaling. JAK2 mediates downstream signaling for type 1 cytokine receptors such as the granulocyte colony stimulating factor receptor (G-CSFR), the erythropoietin receptor (EpoR), and, as exemplified in this figure, the thrombopoietin receptor (MPL). (A) In the normal cell ligand binding leads to phosphorylation of JAK2 and the receptor resulting in downstream phosphorylation of STAT proteins subsequently translocating to the nucleus where transcription of genes involved in cell proliferation and survival is initiated. (B) Mutated JAK2 leads to constitutively activated downstream signaling in the absence of ligand and enhanced signaling in the presence of ligand. (C) The MPL mutations affecting peptide W515, similar to mutations in the JAK2 protein, result in constitutively activated downstream signaling. (D) The novel peptide of the CALR protein, resulting from the +1-frame shift, introduces a new functionality for the CALR protein that leads to CALR-induced homo-dimerization of the MPL receptor and constitutive activation of the receptor. Proteins with mutations are depicted in red; phosphorylation is indicated with a P on yellow background.