Mechanism underlying the development of myeloproliferative neoplasms through mutant calreticulin.

Deregulation of cytokine signaling is frequently associated with various pathological conditions, including malignancies. In patients with myeloproliferative neoplasms (MPNs), recurrent somatic mutations in the calreticulin (CALR) gene, which encodes a molecular chaperone that resides in the endoplasmic reticulum, have been reported. Studies have defined mutant CALR as an oncogene promoting the development of MPN, and deciphered a novel molecular mechanism by which mutant CALR constitutively activates thrombopoietin receptor MPL and its downstream molecules to induce cellular transformation. The mechanism of interaction and activation of MPL by mutant CALR is unique, not only due to the latter forming a homomultimeric complex through a novel mutant-specific sequence generated by frameshift mutation, but also for its ability to interact with immature asparagine-linked glycan for eventual engagement with immature MPL in the endoplasmic reticulum. The complex formed between mutant CALR and MPL is then transported to the cell surface, where it induces constitutive activation of downstream kinase JAK2 bound to MPL. Refined structural and cell biological studies can provide an in-depth understanding of this unusual mechanism of receptor activation by a mutant molecular chaperone. Mutant CALR is also involved in modulation of the immune response, transcription, and intracellular homeostasis, which could contribute to the development of MPN. In the present article, we comprehensively review the current understanding of the underlying molecular mechanisms for mutant molecular chaperone-induced cellular transformation.