Novel molecular mechanism of cellular transformation by a mutant molecular chaperone in myeloproliferative neoplasms

Deregulation of the cytokine‐receptor signaling pathway plays a significant role in tumorigenesis. Such deregulation is frequently caused by alterations in the genes involved in the signaling pathway. At the end of 2013, recurrent somatic mutations in the calreticulin ( CALR ) gene that encodes a molecular chaperone were identified in a subset of patients with Philadelphia‐chromosome negative myeloproliferative neoplasms ( MPN ). The present review focuses on the role of CALR mutations in the oncogenic transformations observed in MPN . All the CALR mutations were found to generate a + 1 frameshift in the reading frame on exon 9, which encodes the carboxy (C)‐terminus end of CALR , and thus conferred a common mutant‐specific sequence in all the CALR mutants. The mutant CALR (but not the wild‐type) constitutively activates the thrombopoietin ( TPO ) receptor, myeloproliferative leukemia protein ( MPL ), even in the absence of TPO to induce cellular transformation. Preferential interaction between the mutant CALR and MPL is achieved by a presumptive conformational change induced by the mutant‐specific C‐terminus domain, which allows N‐domain binding to MPL . Even though mutant CALR is expressed on the cell surface and is secreted out of cells, it only presents autocrine capacity for MPL activation. These findings define a novel molecular mechanism by which the mutant molecular chaperone constitutively activates the cytokine receptor to induce cellular transformation.