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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).

项目总结