Development of myeloproliferative neoplasms by mutant calreticulin: underlying mechanisms

• Published in: Rinshō ketsueki Vol. 59; no. 8; p. 1072
• Main Author: Araki, Marito
• Format: Journal Article
• Language: Japanese
• Published: Japan 2018
• Subjects: Calreticulin - genetics; Endoplasmic Reticulum; Frameshift Mutation; Humans; Myeloproliferative Disorders - genetics; Receptors, Thrombopoietin; Thrombopoietin; MPL; Calreticulin; Chaperone; Myeloproliferative neoplasms
• ISSN: 0485-1439
• DOI: 10.11406/rinketsu.59.1072

Unique frameshift mutations in the calreticulin (CALR) gene, which encodes a molecular chaperone present in the endoplasmic reticulum, were identified in a subset of patients with myeloproliferative neoplasms (MPNs). Recently, it has been reported that mutant CALR constitutively activates the thrombopoietin (TPO) receptor MPL, even in the absence of TPO, thereby inducing cellular transformation. Hence, the tumorigenic role of mutant CALR in the development of MPNs is now clear; nevertheless, the precise molecular mechanism the interaction between mutant CALR and MPL remains elusive. We recently illustrated that the accumulation of mutant CALR in the Golgi apparatus and its N-glycan binding capacity are needed for its tumorigenic capacity, including the interaction and activation of MPL. These findings implied that mutant CALR recognizes MPL during the receptor maturation using its original property as a molecular chaperone. Although the molecular mechanism underlying the activation of MPL by CALR remains elusive, it became clear that the mechanism of interaction between mutant CALR and MPL is quite different from that of TPO, the natural ligand, and MPL.