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The pathophysiology of type 1 versus type 2 mutant calreticulin-drivenmyeloproliferative neoplasms

1 型与 2 型突变钙网蛋白驱动的骨髓增殖性肿瘤的病理生理学

基本信息

批准号：
10503876
负责人：
Shannon Elisabeth Elf
金额：
$ 49.61万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10503876
关键词：
ATF6 gene Acute Myelocytic Leukemia Anabolism Base Pairing Binding Binding Sites Blood Platelets Bone Marrow Bone remodeling C-terminal Calcium Calcium Binding Carbon Cell Compartmentation Cell Death Cell Survival Cells Cellular Stress Response Code Collagen Data Deposition Development Disease Disease Progression Endoplasmic Reticulum Erythrocytes Etiology Exhibits Exons Fibrosis Functional disorder Genes Glycine Hematocrit procedure Hematopoietic Hematopoietic Stem Cell Transplantation Hemoglobin Hemorrhagic Thrombocythemia In Vitro Incidence Inflammation Inflammatory Interleukin-6 JAK2 gene Lead MPL gene Mediating Megakaryocyte Proliferation Megakaryocytes Metabolism Molecular Molecular Abnormality Molecular Chaperones Morbidity - disease rate Mutation Myeloid Cells Myeloproliferative disease Neoplasms Pathogenicity Pathway interactions Patients Peptides Phenotype Polycythemia Vera Primary Myelofibrosis Production Prognosis Proteins Risk Role Serine Signal Transduction Somatic Mutation Stromal Cells Survival Rate Testing Up-Regulation XBP1 gene arm base calreticulin cancer cell cell type clinical phenotype curative treatments cytokine disease phenotype driver mutation endoplasmic reticulum stress granulocyte in vivo individualized medicine inhibitor loss of function mortality mutant novel prognostic proteostasis response sensor stem cells stressor targeted treatment therapeutic target transcription factor treatment strategy

项目摘要

Project Summary Myeloproliferative neoplasms (MPNs) include primary myelofibrosis (PMF; characterized by the over- proliferation of megakaryocytes and granulocytes with abnormal collagen deposition in the bone marrow stroma), essential thrombocythemia (ET; increased megakaryocyte and platelet production), and polycythemia vera (PV; increased red cell production, hemoglobin, and hematocrit). Although all MPN driver mutations lead to constitutive activation of JAK/STAT signaling, targeted JAK inhibitors are not curative and fail to alter disease progression. Therefore, there is a great unmet need to identify novel curative therapies for MPNs. Mutations in calreticulin (CALR) represent the second most common genetic abnormality in MPN. The CALR gene encodes a calcium (Ca2+)-binding chaperone protein that primarily resides in the endoplasmic reticulum (ER). All CALR mutations share an identical neomorphic C-terminal peptide, which permits binding to the thrombopoietin receptor MPL and the subsequent activation of pathogenic JAK/STAT signaling. The majority of CALR mutations are classified as either type 1 or type 2 based on the extent of homology to the wild type protein, where type 1 proteins exhibit complete loss of C-terminal Ca2+ binding sites that are retained in type 2. Despite their shared mutant C-terminus and ability to bind and activate MPL, type 1 and 2 CALR mutations engender significant phenotypic and prognostic differences. Type 1 mutations are more common in PMF, and are associated with increased risk of myelofibrotic transformation from ET. Conversely, type 2 mutations are primarily associated with ET, exhibit low incidence of myelofibrotic transformation, and are rarely found in PMF. The mechanisms underlying these divergent clinical phenotypes remain unknown. We discovered that the IRE1a/XBP1 pathway of the unfolded protein response (UPR) is differentially activated in type 1 versus type 2 mutant CALR cells, and that type 1 mutant CALR cells are dependent on this pathway for survival and to drive ET. We found that IRE1a/XBP1 is activated only by type 1 and not type 2 mutant CALR due to a loss of calcium binding function specific to the type 1 protein. More recently, we found that the ATF6 pathway of the UPR is differentially up- regulated in type 2 compared to type 1 mutant CALR cells, and that type 2 mutant proteins exhibit loss of molecular chaperone function. These data support the central hypothesis that type 1 and type 2 CALR mutations activate and depend on different arms of the UPR based on their respective losses of function, and that these pathways promote distinct disease phenotypes. Thus, targeting different arms of the UPR based on mutation type may represent a novel, individualized treatment strategy for type 1 versus type 2 CALR+ MPN patients. To test this hypothesis, we will dissect the role of the UPR in type 1 mutant CALR-driven fibrosis (Specific Aim 1) and type 2 mutant CALR-driven ET (Specific Aim 2), and determine if each is uniquely sensitive to therapeutic targeting of different arms of the UPR (Specific Aim 3).

项目概要骨髓增生性肿瘤（MPN）包括原发性骨髓纤维化（PMF；其特征是过度骨髓纤维化）巨核细胞和粒细胞增殖，骨髓基质中胶原沉积异常），原发性血小板增多症（ET；巨核细胞和血小板生成增多）和真性红细胞增多症（PV；增加红细胞生成、血红蛋白和血细胞比容）。尽管所有 MPN 驱动突变都会导致 JAK/STAT 信号传导的组成型激活，靶向 JAK 抑制剂无法治愈且无法改变疾病进展。因此，寻找新的 MPN 治疗方法的需求尚未得到满足。突变在钙网蛋白 (CALR) 是 MPN 中第二常见的遗传异常。 CALR基因编码一种主要存在于内质网 (ER) 中的钙 (Ca2+) 结合伴侣蛋白。所有CALR 突变共享相同的新形态 C 端肽，允许与血小板生成素结合受体 MPL 以及随后致病性 JAK/STAT 信号传导的激活。大多数 CALR 突变根据与野生型蛋白的同源性程度，将其分为 1 型或 2 型，其中 1 型蛋白质表现出 C 端 Ca2+ 结合位点的完全丧失，而这些结合位点保留在 2 型中。突变的 C 末端以及结合和激活 MPL、1 型和 2 型 CALR 突变的能力会产生显着的影响表型和预后差异。 1 型突变在 PMF 中更常见，并且与 ET 导致骨髓纤维化的风险增加。相反，2 型突变主要与与 ET 相比，骨髓纤维化转化的发生率较低，并且很少见于 PMF。机制这些不同的临床表型背后的原因仍然未知。我们发现 IRE1a/XBP1 通路未折叠蛋白反应 (UPR) 在 1 型与 2 型突变 CALR 细胞中的激活存在差异，并且 1 型突变 CALR 细胞依赖于该途径生存并驱动 ET。我们发现由于钙结合功能丧失，IRE1a/XBP1 仅被 1 型突变体 CALR 激活，而不会被 2 型突变体 CALR 激活特定于 1 型蛋白质。最近，我们发现 UPR 的 ATF6 通路存在差异性上调：与 1 型突变 CALR 细胞相比，2 型突变蛋白受到调节，并且 2 型突变蛋白表现出分子伴侣功能。这些数据支持中心假设：1 型和 2 型 CALR 突变根据各自的功能丧失而激活并依赖于 UPR 的不同臂，并且这些途径促进不同的疾病表型。因此，针对普遍定期审议的不同分支，突变类型可能代表 1 型与 2 型 CALR+ MPN 的新型个体化治疗策略患者。为了验证这一假设，我们将剖析 UPR 在 1 型突变 CALR 驱动的纤维化中的作用（具体目标 1）和 2 型突变体 CALR 驱动的 ET（具体目标 2），并确定每个突变体是否唯一对 UPR 不同分支的治疗目标敏感（具体目标 3）。