Lineages and pathophysiology of clonal histiocytic disorders

克隆组织细胞疾病的谱系和病理生理学

• 批准号: 10001080
• 负责人: Frederic Geissmann
• 金额: $ 71.29万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-16 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001080
• 关键词: Adult; Affect; Alleles; BRAF gene; Birth; Bone Marrow; Brain; Characteristics; Chromatin; Clinical; Complication; Development; Diagnosis; Diagnostic; Disease; Embryo; Embryonic Development; Environmental Risk Factor; Eosinophilic Granuloma; Erdheim-Chester Disease; Erythro; Functional disorder; Gene Expression Profile; Genetic Models; Genetic Transcription; Goals; Hematopoietic stem cells; Heterogeneity; Histiocytosis; Human Characteristics; Kupffer Cells; Laboratories; Lesion; Leukocytes; Liver; Liver Fibrosis; Microglia; Modeling; Molecular; Mus; Mutation; Myelogenous; Myeloid Cells; Neoplasms; Nerve Degeneration; Neurodegenerative Disorders; Organogenesis; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Pulmonary Fibrosis; Refractory; Role; Somatic Mutation; Syndrome; Testing; Time; Tissues; Work; Yolk Sac; base; brain cell; experimental study; histiocyte; improved; in vivo; in vivo Model; inhibitor/antagonist; interest; macrophage; monocyte; mouse model; new therapeutic target; novel; novel therapeutic intervention; outcome forecast; prevent; progenitor; prognostic; residence; stem

Project Summary This project aims to characterize at the molecular, cellular and organismal levels the pathophysiology of clonal histiocytic disorders, exemplified by Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD). These diseases display a considerable heterogeneity in terms of prognostic and clinical presentation, and are characterized by the occurrence of neurodegenerative syndromes and liver and lung fibrosis, the mechanisms of which are mysterious. Their pathophysiology is largely unknown. Two recent discoveries offer an opportunity to re-evaluate the pathophysiology and molecular underpinning of clonal histiocytic disorders, improve their diagnostic, prognostic, and offer new therapeutic strategies. First, the discovery of somatic mutations of the RAS-ERK pathway in >70% of cases of LCH and ECD by us and others has led to new therapeutic approaches based on the use of BRAF inhibitors and has renewed interests in efforts toward solving the pathophysiology of these diseases. Second, an important revision of our understanding of myeloid development stems from recent works from our laboratory and others which have revealed that the tissue- resident macrophages found in adult mice originate from early hematopoietic progenitors from the yolk sac independent of hematopoietic stem cells (HSCs) and persist within their tissue of residence in adults. Following on this work, we made the novel hypothesis that somatic BRAF mutations in yolk sac progenitors may causes histiocytoses and we have developed in vivo models that allow to test this hypothesis experimentally. Our preliminary results indicate that conditional expression of a BRAFV600E allele in yolk sac hematopoietic progenitors in vivo does results in the accumulation of BRAFV600E macrophage clones in various tissues, and is responsible in particular for a neurodegenerative syndrome in adult mice, that recapitulates for the first time one of the most intriguing and adverse phenotypic characteristics of the human histiocytic neoplasms. We will (Aim 1) will investigate the molecular and cellular mechanisms that underlie the development of brain neurodegenerative disease and identify molecular pathways that drive pathological histiocytes, (Aim 2) determine the pathological roles of BRAFV600E macrophages outside the brain in vivo and in particular in liver fibrosis, and (Aim 3) investigate the efficiency of BRAF inhibitor administration in the murine models. These experiments will provide a proof of concept that a mutations in yolk sac progenitors can cause an histiocytic disease in adults, help elucidate the pathophysiology and mechanism of histiocytoses and some of their most adverse complication such as the neurodegenerative syndrome, and reveal novel therapeutic targets to be used in conjunction with, or alternatively to, BRAF inhibitors.

项目摘要 本项目旨在从分子、细胞和组织水平表征克隆的病理生理学。 组织细胞疾病，例如朗格汉斯细胞组织细胞增生症(LCH)和埃尔德海姆-切斯特病(ECD)。 这些疾病在预后和临床表现方面表现出相当大的异质性，并且 以神经退行性综合征和肝肺纤维化的发生为特征，其机制 其中有一些是神秘的。他们的病理生理学在很大程度上是未知的。最近的两项发现提供了一个机会 为重新评估克隆性组织细胞疾病的病理生理学和分子基础，改进其 诊断、预测和提供新的治疗策略。首先，发现了人的体细胞突变 我们等人在70%的LCH和ECD病例中发现了RAS-ERK通路，从而导致了新的治疗方法 以使用BRAF抑制剂为基础的方法，并重新对努力解决 这些疾病的病理生理学。第二，对我们对髓系的理解进行了重要的修订 这项研究源于我们实验室和其他实验室最近的研究，它们揭示了组织- 在成年小鼠体内发现的常驻巨噬细胞来自卵黄囊的早期造血祖细胞 不依赖于造血干细胞(HSCs)，并持续存在于成人的居住组织中。 在这项工作之后，我们提出了一个新的假设，即卵黄囊祖细胞中的体细胞BRAF突变 可能会导致组织细胞增多症，我们已经开发出体内模型，可以检验这一假说 试验性的。我们的初步结果表明，BRAFV600E等位基因在卵黄囊中有条件表达 体内造血祖细胞确实导致BRAFV600E巨噬细胞克隆在不同的 组织，特别是对成年小鼠的一种神经退行性综合征负责，概括为 首次发现人类组织细胞最耐人寻味和最不利的表型特征之一 肿瘤。 我们将(目标1)研究大脑发育的分子和细胞机制。 神经退行性疾病和确定驱动病理性组织细胞的分子途径(目标2) 确定BRAFV600E巨噬细胞在脑外，特别是肝脏中的病理作用 目的3)研究BRAF抑制剂在小鼠模型中的应用效果。 这些实验将提供一个概念的证据，即卵黄囊前体细胞的突变可以导致 成人组织细胞性疾病，有助于阐明组织细胞增多症的病理生理学和机制，以及一些 他们最不利的并发症，如神经退行性综合征，并揭示了新的治疗方法 与BRAF抑制剂联合使用或替代使用的靶点。

项目成果

Hematopoietic Somatic Mosaicism Is Associated With an Increased Risk of Postoperative Atrial Fibrillation.

• DOI: 10.1016/j.jacc.2023.01.036
• 发表时间: 2023-04
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: S. Ninni;D. Dombrowicz;Tanya Kuznetsova;Rocio Vicario;Vance Gao;O. Molendi-Coste;Joel T. Haas;E. Woitrain;A. Coisne;A. Neele;K. Prange;Lisa Willemsen;S. Aghezzaf;Stamatina Fragkogianni;Amine Tazibet;L. Pineau;J. White;J. Eeckhoute;M. Koussa;Henri Dubrulle;F. Juthier;J. Soquet;A. Vincentelli;J. Edmé;M. D. de Winther;F. Geissmann;B. Staels;D. Montaigne

Diet-regulated production of PDGFcc by macrophages controls energy storage.

• DOI: 10.1126/science.abe9383
• 发表时间: 2021-07-02
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Cox, Nehemiah;Crozet, Lucile;Holtman, Inge R.;Loyher, Pierre-Louis;Lazarov, Tomi;White, Jessica B.;Mass, Elvira;Stanley, E. Richard;Elemento, Olivier;Glass, Christopher K.;Geissmann, Frederic
• 通讯作者: Geissmann, Frederic

Selective Nanoparticle Targeting of the Renal Tubules.

• DOI: 10.1161/hypertensionaha.117.09843
• 发表时间: 2018-01
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Williams RM;Shah J;Tian HS;Chen X;Geissmann F;Jaimes EA;Heller DA
• 通讯作者: Heller DA

Yolk sac macrophage progenitors traffic to the embryo during defined stages of development.

• DOI: 10.1038/s41467-017-02492-2
• 发表时间: 2018-01-08
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Stremmel C;Schuchert R;Wagner F;Thaler R;Weinberger T;Pick R;Mass E;Ishikawa-Ankerhold HC;Margraf A;Hutter S;Vagnozzi R;Klapproth S;Frampton J;Yona S;Scheiermann C;Molkentin JD;Jeschke U;Moser M;Sperandio M;Massberg S;Geissmann F;Schulz C
• 通讯作者: Schulz C

Macrophages of distinct origins contribute to tumor development in the lung.

• DOI: 10.1084/jem.20180534
• 发表时间: 2018-10-01
• 期刊: The Journal of experimental medicine
• 作者: Loyher PL;Hamon P;Laviron M;Meghraoui-Kheddar A;Goncalves E;Deng Z;Torstensson S;Bercovici N;Baudesson de Chanville C;Combadière B;Geissmann F;Savina A;Combadière C;Boissonnas A
• 通讯作者: Boissonnas A