The role of calreticulin mutations in myeloproliferative neoplasms


Unique frameshift mutations in the calreticulin (CALR) gene, which encodes an endoplasmic reticulum (ER)-localized molecular chaperone, have been identified in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), which are subgroups of myeloproliferative neoplasms (MPNs). In this review, we discuss the current understanding of the consequences of these mutations with regard to tumorigenesis and/or signal transduction. Expression of mutant CALR induces thrombocytosis in animal models, producing the phenotype of ET. Mutant CALR preferentially interacts with and activates the thrombopoietin receptor MPL, resulting in MPL-dependent cellular transformation. A novel carboxyl-terminal sequence generated by a frameshift mutation in CALR mediates intermolecular interactions to form homomultimers and induces structural changes required for MPL binding and activation. The homomultimerized mutant CALR behaves similarly to a cytokine, stabilizing homodimerized MPL by binding to immature MPL N-glycans. Mutant CALR may engage with MPL in the ER, but fails to dissociate, conveying MPL to the cell surface where MPL activation is likely to occur. Collectively, cell-autonomous and constitutive activation of MPL is a cause of MPNs that are mediated by mutant CALR. Novel therapeutic strategies for treating MPNs that target these mechanisms should, therefore, be developed.

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This work was funded in part by the MEXT-Supported Program for the Strategic Research Foundation at Private Universities; MEXT’s Promotion Plan for the Platform of Human Resource Development for Cancer Project; the JSPS KAKENHI Grant #16K09859, #17H04211, #18K08372, #19K08848; grants from the Takeda Science Foundation, the SENSHIN Medical Research Foundation and the Japan Leukemia Research Fund. The funders had no role in the preparation of the manuscript.

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Correspondence to Norio Komatsu.

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Araki, M., Komatsu, N. The role of calreticulin mutations in myeloproliferative neoplasms. Int J Hematol 111, 200–205 (2020).

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  • Myeloproliferative neoplasms
  • Calreticulin
  • Thrombopoietin receptor
  • JAK2