A New Murine Model for MPN: Pathololgy and Therapy of NF-E2 Overexpression

MPN 的新小鼠模型：NF-E2 过度表达的病理学和治疗

• 批准号: 8377870
• 负责人: Heike L Pahl
• 金额: $ 38.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8377870
• 关键词: Abnormal megakaryocyte; Acute leukemia; Age; Age-Months; Autopsy; Bone Marrow; Characteristics; Data; Development; Diagnosis; Disease; Disease susceptibility; Erythroid; Ethylnitrosourea; Evolution; Frequencies; Functional disorder; Growth; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Histology; Hyperplasia; Instruction; Intervention; JAK2 gene; Knowledge; Modeling; Molecular; Morphology; Mus; Mutagens; Mutation; Myelogenous; Myeloproliferative disease; Pathologic; Patients; Phase; Phase I Clinical Trials; Phenotype; Predisposition; Proteins; Research; Risk; Role; Splenomegaly; Stem cells; Thrombosis; Transgenic Mice; Transgenic Organisms; Transplantation; base; in vivo; mortality; mouse model; novel therapeutics; nuclear factor-erythroid 2; outcome forecast; overexpression; pre-clinical; precursor cell; promoter; thrombocytosis; transcription factor; treatment strategy

Despite recent advances in our understanding of the development of Myeloproliferative Neoplasms (MPNs), the pathophysiology of these disorders remains poorly understood. Especially the predisposition of MPN patients to transform to acute leukemia is not elucidated. Based on our observation that the transcription factor nuclear factor erythroid 2 (NF-E2) is overexpressed in the majority of MPN patients, we have established a murine model for MPNs, by overexpressing NF-E2 in vivo. Besides the JAK2 V617F and c-MpI W515X mouse models, this is the only murine model of MPN that employs a molecular aberration observed in MPN patients. NF-E2 was overexpressed in all hematopoietic lineages including hematopoietic progenitor cells. Two independently generated founder lines show a phenotype with many features of MPNsj including thrombocytosis, splenomegaly and MPN-like changes in bone marrow (BM) histology. The number of BM erythroid, myeloid and megakaryocytic precursors are significantly increased in NF-E2 transgenic (tg) mice, notably the number of autonomous, EPO-independent erythroid colonies. EPO-independent colonies are a pathognomonic hallmark of MPN patients. NF-E2 transgenic mice display significantly increased mortality with autopsy findings resembling those of MPN patients including splanchnic thrombosis and bleeding diatheses. At 20 months of age, one mouse (7.6%) developed acute leukemia. Our murine model therefore displays a phenotype closely resembling many features of MPN. In addition, our preliminary data indicate that NF-E2 overexpression may predispose to the development of acute leukemia. Based on this data, we formulate the following hypotheses: Hypothesis 1: NF-E2 overexpression alters hematopoietic stem cells (HSCs) resulting in the development of an MPN phenotype. NF-E2 overexpression causes cellautonomous changes in HSCs, the phenotype is therefore transplantable and constitutes a hematopoietic stem cell disorder. Specific Aim 1: To perform primary and secondary transplants and to characterize the stem cell compartment of NF-E2 transgenic donor and recipient mice. Hypothesis 2: NF-E2 overexpression constitutes a pre-leukemic state and predisposes to the evolution to acute leukemia. Specific Aim 2: To treat NF-E2 transgenic and control mice with the mutagen N-ethyl-N-nitrosourea ENU and observe the frequency of leukemic transformation. Hypothesis 3: The pathophysiological changes evoked by NF-E2 overexpression are treatable by pharmacologic intervention. Specific Aim 3: To treat NF-E2 transgenic mice with pharmacological agents currently in pre-clinical or phase I clinical trials for MPN patients.

尽管我们对骨髓增生性肿瘤（MPN）的发展有了新的认识，但这些疾病的病理生理学仍然知之甚少。特别是MPN患者转化为急性白血病的易感性尚未阐明。基于我们观察到转录因子核因子红细胞2（NF-E2）在大多数MPN患者中过表达，我们通过体内过表达NF-E2建立了MPN的鼠模型。除了JAK 2 V617 F和c-MpI W515 X小鼠模型之外，这是唯一一种采用在MPN患者中观察到的分子畸变的MPN鼠模型。NF-E2在包括造血祖细胞在内的所有造血谱系中过表达。两个独立产生的建立者系显示具有MPNs的许多特征的表型，包括血小板增多、脾肿大和骨髓（BM）组织学中的MPN样变化。在NF-E2转基因（tg）小鼠中，BM红细胞、髓细胞和巨核细胞前体细胞的数量显著增加，特别是自主的、EPO非依赖性红细胞集落的数量。EPO非依赖性集落是MPN患者的特征性标志。NF-E2转基因小鼠的死亡率显着增加，尸检结果类似于MPN患者，包括内脏血栓形成和出血素质。在20个月大时，一只小鼠（7.6%）发生急性白血病。因此，我们的小鼠模型显示出与MPN的许多特征非常相似的表型。此外，我们的初步数据表明，NF-E2过表达可能易患急性白血病的发展。基于这些数据，我们提出了以下假设：假设1：NF-E2过表达改变造血干细胞（HSC），导致MPN表型的发展。NF-E2过表达导致HSC中的细胞凋亡变化，因此表型是可移植的并且构成造血干细胞病症。具体目标1：进行初次和二次移植，并表征NF-E2转基因供体和受体小鼠的干细胞区室。假设2：NF-E2过表达构成白血病前状态，并易于演变为急性白血病。具体目标二：用诱变剂N-乙基-N-亚硝基脲ENU处理NF-E2转基因小鼠和对照小鼠，观察白血病转化率。假设3：由NF-E2过度表达引起的病理生理变化可通过药物干预治疗。具体 目的3：用目前处于临床前或I期临床试验的药物治疗MPN患者的NF-E2转基因小鼠。