Investigating the role of Nol3 in normal and malignant hematopoiesis

研究 Nol3 在正常和恶性造血中的作用

基本信息

批准号：
9889052
负责人：
Richard Piszczatowski
金额：
$ 5.05万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889052
关键词：
Acute Myelocytic Leukemia Anemia Apoptosis Binding Biological Assay Blood Cells Bone Marrow CBL gene Caspase Cell Differentiation process Cell Line Cell Lineage Cell physiology Cells Characteristics Chimeric Proteins Chromosomes Chronic Myeloid Leukemia Co-Immunoprecipitations Cytoplasm Data Development Disease Disease Progression Event Exhibits Genes Genetic Goals Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic System Hematopoietic stem cells Hemorrhagic Thrombocythemia High Dose Chemotherapy Human In Vitro Intervention JAK2 gene Lead Lesion Link Malignant - descriptor Modeling Molecular Morbidity - disease rate Mus Mutation Myelofibrosis Myelogenous Myeloid Cells Myeloproliferative disease Nucleolar Proteins Oncogenic Pathogenesis Pathway interactions Patients Peripheral Phenotype Philadelphia Philadelphia Chromosome Play Polycythemia Vera Population Predisposing Factor Primary Myelofibrosis Process Production Proteins Proto-Oncogene Protein c-kit Publishing Relapse Rest Risk Role Sampling Signal Pathway Signal Transduction Spleen Splenomegaly Study models Testing Therapeutic Time Transplantation Tumor Suppressor Proteins acute myeloid leukemia cell base bcr-abl Fusion Proteins blood formation congenic curative treatments cytopenia driver mutation experimental study hematopoietic stem cell differentiation human disease in vivo insight leukemia leukemic transformation molecular pathology mortality mouse model myeloblast novel novel strategies novel therapeutics peripheral blood prevent protein protein interaction recruit self-renewal targeted treatment

项目摘要

Abstract Hematopoiesis relies on the proper function of hematopoietic stem and progenitor cells (HSPCs), in their capacity for both self-renewal and differentiation. Genetic lesions in these cell populations can give rise to myeloid malignancies including myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). Myeloproliferative neoplasms, which result in the expansion of mature myeloid compartments, commonly harbor aberrations or mutations involving the JAK/STAT signaling pathway. Mutations in JAK2, CALR, and MPL are found in the majority of MPN cases, however cooperating co-driver mutations and disease modifiers are relatively poorly understood. Current treatment options for Philadelphia-chromosome-negative (Ph-) MPNs provide symptomatic relief and do not significantly alter overall survival. Moreover, leukemic transformation to AML is a common occurrence in Ph- MPN patients, and is thought to be due to acquisition of additional mutations which ultimately lead to a dramatic reduction in patient survival. The process of leukemic transformation of MPN to AML still remains unclear, and gaining insight into the molecular mechanisms of this phenomenon may provide openings for new interventions for preventing disease progression. We have discovered that loss of the Nol3 gene in mice leads to an MPN-like disease closely resembling primary myelofibrosis (PMF). Paradoxical to its canonical functions in repressing apoptosis, deletion of Nol3 results in an increased expansion and cycling of HSPCs in the bone marrow and spleen, suggesting a novel role for Nol3 within the hematopoietic system. Our analyses show that Nol3 is frequently downregulated or deleted in patients with PMF and other myeloid malignancies, and our data provides a link between Nol3 expression and JAK/STAT activation in MPN and AML cells, implicating Nol3 in the JAK/STAT signaling pathway. Our proposal seeks to (1) characterize the molecular role of Nol3 in hematopoiesis by defining molecular functions and subcellular localization, as well as identifying functional binding partners, (2) relate Nol3 loss to human disease by dissecting the role of Nol3 within the JAK/STAT pathway and identifying critical functional domains, and (3) gain insight into cooperativity between Nol3 loss and mutational drivers in MPN and transformation to AML. Our study will not only provide a novel and robust model for studying myeloid malignancies, but will also help define for the first time a role for Nol3 as a myeloid tumor suppressor and key component of the JAK/STAT signaling pathway. More importantly, our studies will also link Nol3 to human myeloid malignancy, which will provide a deeper understanding of the molecular pathogenesis of disease.

抽象的造血依赖于造血干细胞和祖细胞（HSPC）的正常功能，他们的自我更新和分化能力。这些细胞群中的基因损伤可能会导致骨髓恶性肿瘤，包括骨髓增生性肿瘤（MPN）和急性髓系白血病（AML）。骨髓增生性肿瘤通常会导致成熟骨髓区的扩张含有涉及 JAK/STAT 信号通路的畸变或突变。 JAK2、CALR 和 MPL 存在于大多数 MPN 病例中，但协同驱动突变和疾病修饰因素的了解相对较少。目前费城染色体阴性 (Ph-) MPN 的治疗选择缓解症状并且不会显着改变总体生存率。此外，白血病转变为 AML 在 Ph-MPN 患者中很常见，被认为是由于获得了额外的最终导致患者生存率急剧下降的突变。白血病的过程 MPN 向 AML 的转化仍不清楚，需要深入了解其分子机制这种现象可能为预防疾病进展的新干预措施提供机会。我们发现小鼠中 Nol3 基因的缺失会导致类似 MPN 的疾病类似于原发性骨髓纤维化（PMF）。与其抑制细胞凋亡的典型功能相反， Nol3 的缺失导致骨髓和脾脏中 HSPC 的扩增和循环增加，表明 Nol3 在造血系统中的新作用。我们的分析表明 Nol3 经常被 PMF 和其他骨髓恶性肿瘤患者中下调或删除，我们的数据提供了一个链接 MPN 和 AML 细胞中 Nol3 表达与 JAK/STAT 激活之间的关系，表明 Nol3 在 JAK/STAT 中信号通路。我们的建议旨在 (1) 通过定义来描述 Nol3 在造血过程中的分子作用分子功能和亚细胞定位，以及识别功能性结合伴侣，(2) 通过剖析 Nol3 在 JAK/STAT 通路中的作用并确定关键的 Nol3 缺失对人类疾病的影响功能域，以及 (3) 深入了解 MPN 中 Nol3 丢失和突变驱动因素之间的协同作用以及向 AML 的转变。我们的研究不仅将为研究骨髓细胞提供一种新颖而稳健的模型恶性肿瘤，但也将有助于首次确定 Nol3 作为骨髓肿瘤抑制因子和关键因子的作用 JAK/STAT 信号通路的组成部分。更重要的是，我们的研究还将Nol3与人类联系起来骨髓恶性肿瘤，这将使人们更深入地了解疾病的分子发病机制。