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.

中文翻译：

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钙网蛋白突变在骨髓增生性肿瘤中的作用。

已在患有原发性血小板增多症（ET）和原发性骨髓纤维化（PMF）的患者中鉴定了钙网蛋白（CALR）基因中编码内质网（ER）定位的分子伴侣的独特移码突变，它们是骨髓增生性肿瘤（MPNs）的子组）。在这篇综述中，我们讨论了关于这些突变对肿瘤发生和/或信号转导的影响的当前理解。突变CALR的表达在动物模型中诱导血小板增多，产生ET的表型。突变的CALR优先与血小板生成素受体MPL相互作用并激活其，从而导致MPL依赖性细胞转化。由CALR中的移码突变产生的新的羧基末端序列介导了分子间的相互作用以形成同型多聚体，并诱导了MPL结合和激活所需的结构变化。同源多聚突变体CALR的行为类似于细胞因子，通过结合未成熟的MPL N-聚糖来稳定同源二聚化的MPL。突变的CALR可能与ER中的MPL结合，但无法解离，将MPL传递至可能发生MPL活化的细胞表面。总的来说，MPL的细胞自主性和组成性激活是由突变CALR介导的MPN的原因。因此，应开发出针对这些机制的MPN的新型治疗策略。通过与未成熟的MPL N-聚糖结合来稳定均二聚化的MPL。突变的CALR可能与ER中的MPL结合，但无法解离，将MPL传递至可能发生MPL活化的细胞表面。总的来说，MPL的细胞自主性和组成性激活是由突变CALR介导的MPN的原因。因此，应开发出针对这些机制的MPN的新型治疗策略。通过与未成熟的MPL N-聚糖结合来稳定均二聚化的MPL。突变的CALR可能与ER中的MPL结合，但无法解离，将MPL传递至可能发生MPL活化的细胞表面。总的来说，MPL的细胞自主性和组成性激活是由突变CALR介导的MPN的原因。因此，应开发出针对这些机制的MPN的新型治疗策略。