Defining Pathogenic Mechanisms and Therapeutic Opportunities for Langerhans Cell Histiocytosis

项目摘要 这是第二次有竞争力的赠款申请，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是一种以肉芽肿性病变为特征的疾病， MAPK途径中具有激活体细胞突变的克隆性CD207 + CD1a+单核吞噬细胞（MNP） 基因，尤其是BRAFV600E。临床表现是高度可变的，从自我解决的单一病变，以致命的 传播性疾病。LCH患者的最佳治疗策略仍然是一个主要的未满足的需求。我们提出 以确定细胞起源、携带活化MAPK通路突变的细胞分化以及 靶组织对发病机制的影响，以确定和测试新的治疗策略， LCH患者的结局。扩大这项合作研究计划的总体目标是， 确定致病机制，确定和测试治疗策略，以改善患者的预后， lch豪华 具体目标1： 确定细胞来源、年龄、MAPK突变和微环境（ME）的作用 疾病的程度。在以前研究的基础上，我们建议测试起源细胞的相对作用， MAPK突变与靶组织中的血液学和基质微环境在确定疾病程度中的作用 和临床表型。 具体目标2：确定细胞衰老程序对LCH发病机制的贡献， 临床结果。早期HPC中BRAF突变导致LCH疾病的发现使我们探索原因 以及表达BRAFV600E突变的早期HPC如何导致外周LCH病变。引人注目的是，我们 发现HPC中的BRAF突变诱导衰老程序，增强小鼠和人类HPC 分化为LCH样细胞。我们发现BRAF突变的HPC和LCH细胞表达典型的 包括高水平的细胞周期抑制剂CDKN 2a，抗凋亡分子Bcl-xL， 增加mTOR活性和衰老相关分泌蛋白（SASP），促进累积 长寿命的炎性LCH样细胞在组织中。因此，我们将测试衰老的贡献 LCH疾病的结果。 具体目标3：测试衰老清除药物在LCH治疗中的益处。我们将测试 两种衰老清除疗法，包括单独的BH3模拟物和与化疗和MAPK组合， 抑制LCH。

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.