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, Tokyo, Japan.
Leukemia. 2019 Jan;33(1):122-131. doi: 10.1038/s41375-018-0181-2. Epub 2018 Jun 26.
Studies have previously shown that mutant calreticulin (CALR), found in a subset of patients with myeloproliferative neoplasms (MPNs), interacts with and subsequently promotes the activation of the thrombopoietin receptor (MPL). However, the molecular mechanism behind the activity of mutant CALR remains unknown. Here we show that mutant, but not wild-type, CALR interacts to form a homomultimeric complex. This intermolecular interaction among mutant CALR proteins depends on their carboxyl-terminal domain, which is generated by a unique frameshift mutation found in patients with MPN. With a competition assay, we demonstrated that the formation of mutant CALR homomultimers is required for the binding and activation of MPL. Since association with MPL is required for the oncogenicity of mutant CALR, we propose a model in which the constitutive activation of the MPL downstream pathway by mutant CALR multimers induces the development of MPN. This study provides a potential novel therapeutic strategy against mutant CALR-dependent tumorigenesis via targeting the intermolecular interaction among mutant CALR proteins.
先前的研究表明，在骨髓增生性肿瘤（MPN）的一部分患者中发现的突变钙网织蛋白（CALR）与血小板生成素受体（MPL）相互作用，并随后促进其激活。然而，突变型 CALR 活性背后的分子机制尚不清楚。在这里，我们表明突变型而非野生型 CALR 相互作用形成同源三聚体复合物。这种突变型 CALR 蛋白之间的分子间相互作用依赖于其羧基末端结构域，该结构域是由 MPN 患者中发现的独特移码突变产生的。通过竞争测定，我们证明了突变型 CALR 同源三聚体的形成对于 MPL 的结合和激活是必需的。由于与 MPL 的关联是突变型 CALR 致癌性所必需的，因此我们提出了一种模型，即突变型 CALR 三聚体的 MPL 下游途径的组成性激活诱导 MPN 的发展。这项研究提供了一种通过靶向突变型 CALR 蛋白之间的分子间相互作用来对抗突变型 CALR 依赖性肿瘤发生的潜在新型治疗策略。
