Defining Pathogenic Mechanisms and Therapeutic Opportunities for Langerhans Cell Histiocytosis

项目总结 这是第二次竞争性续期的基金申请，以确定病理生理学和治疗 朗格汉斯细胞组织细胞增生症(LCH)。LCH是一种以肉芽肿性皮损为特征的疾病 活化MAPK途径体细胞突变的克隆性CD207+CD1a+单核巨噬细胞 基因，最著名的是BRAFV600E。临床表现千差万别，从可自行解决的单个病变到致死。 播散性疾病。LCH患者的最佳治疗策略仍然是一个主要的未得到满足的需求。我们建议 目的：明确MAPK通路基因突变的细胞来源、细胞分化以及MAPK信号转导途径的作用。 靶组织对发病机制的影响，以确定和测试新的治疗策略以改善 LCH患者的预后。扩展这一合作研究计划的总体目标是 明确发病机制，确定和测试治疗策略，以改善患者的预后 啊哈。 具体目标1： 确定起源细胞、年龄、MAPK突变和微环境(ME)的作用 关于疾病的程度。在以往研究的基础上，我们建议测试来源细胞在 MAPK突变与靶组织血液学和间质微环境在判断疾病程度中的作用 和临床表型。 特定目的2：确定细胞衰老程序在LCH发病机制中的作用 临床结果。早期HPC中BRAF突变导致LCH疾病的发现使我们探索为什么 以及表达BRAFV600E突变的HPC早期如何导致外周LCH病变。令人惊讶的是，我们 发现HPC中的BRAF突变诱导了一种增强小鼠和人类HPC的衰老程序 分化为LCH样细胞。我们发现BRAF突变的HPC和LCH细胞表达规范 衰老程序包括高水平的细胞周期抑制物CDKN2A，抗凋亡分子Bcl-xL， 增加mTOR活性和促进积累的衰老相关分泌蛋白(SASP) 组织中长期存活的炎性LCH样细胞。因此，我们将检验衰老的贡献 LCH疾病结局的计划。 具体目的3：检测抗衰老药物在LCH治疗中的作用。我们将测试其治疗潜力 包括BH3模拟物单独和与化疗和MAPK联合使用的两种感光疗法 对LCH的抑制作用。

Project summary This is the second competitive renewal of a grant application to identify the pathophysiology and treatment of Langerhans cell histiocytosis (LCH). LCH is a disease characterized by granulomatous lesions with characteristic clonal CD207+ CD1a+ mononuclear phagocytes (MNP) with activating somatic mutations in MAPK pathway genes, most notably BRAFV600E. Clinical presentations are highly variable, from self-resolving single lesions to fatal disseminated disease. Optimal therapeutic strategies for patients with LCH remain a major unmet need. We propose to define the roles of cell of origin, differentiation of cells harboring activating MAPK pathway mutations, and the impact of target tissue on pathogenesis in order to identify and test novel therapeutic strategies to improve outcomes for patients with LCH. The overall goal of expanding on this collaborative research program is to define pathogenic mechanisms and identify and test therapeutic strategies to improve outcomes of patients with LCH. Specific Aim 1: To determine the roles of cell of origin, age, MAPK mutation, and microenvironment (ME) on extent of disease. Building on previous studies, we propose to test the relative role of the cell of origin of the MAPK mutation and hematologic and stroma microenvironment in target tissues in defining extent of disease and clinical phenotype. Specific Aim 2: To identify the contribution of cellular senescence program to LCH pathogenesis and clinical outcomes. The finding that BRAF mutation in early HPC leads to LCH disease led us to explore why and how early HPC expressing BRAFV600E mutations can lead to LCH lesions in the periphery. Strikingly, we found that BRAF mutations in HPC induce a senescence program that enhances mouse and human HPC differentiation into LCH-like cells. We found that BRAF-mutated HPC and LCH cells expressed canonical senescence program including high levels of the cell cycle inhibitor CDKN2a, the antiapoptotic molecule Bcl-xL, increased mTOR activity and senescence associated secretory proteins (SASP) that promote the accumulation of long lived inflammatory LCH-like cells in tissues. Therefore, we will test the contribution of the senescence program to LCH disease outcome. Specific Aim 3: To test the benefit of senolytic drugs in LCH treatment. We will test the therapeutic potential of two senolytic therapies including BH3 mimetics alone and in combination with chemotherapy and MAPK inhibition for LCH.