The role of calreticulin mutations in myeloproliferative neoplasms
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PROGRESS IN HEMATOLOGY Progress in elucidation of molecular pathophysiology and its application to therapeutic decisions of MPNs
The role of calreticulin mutations in myeloproliferative neoplasms Marito Araki1 · Norio Komatsu2 Received: 20 May 2019 / Revised: 9 December 2019 / Accepted: 10 December 2019 © Japanese Society of Hematology 2019
Abstract 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. Keywords Myeloproliferative neoplasms · Calreticulin · Thrombopoietin receptor · JAK2
Introduction The pathogenesis of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), which include three major disease subgroups: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), has been clarified following the identification of underlying recurrent somatic mutations and the functional characterization of the genes containing these mutations. A V617F mutation was first identified on a gene encoding janus kinase 2 (JAK2) in patients with MPN in 2005 [1-4]. Soon after, myeloproliferative leukemia protein (MPL) W515K/L [5, 6] * Norio Komatsu [email protected] 1
Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine, Tokyo, Japan
Department of Hematology, Juntendo University Graduate School of Medicine, 2‑1‑1 Hongo, Bunkyo‑ku, Tokyo 113‑8421, Japan
2
and JAK2 exon 12 [7] mutations were identified in ET and PMF, and PV patients, respectively. Functional characterization of these mutant genes defined them as driver mutations for MPN [8], implying that activation of the MPL-JAK2 axis is a cause of MPN, and that activation of other receptor caused by the JAK2 mutation contributes to the d
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