Redefining Langerhans Cell Histiocytosis as a Myeloid Dysplasia and Identifying B

描述(申请人提供)：将朗格汉斯细胞组织细胞增生症重新定义为骨髓细胞异常增生症，并确定用于早期检测和风险评估的生物标记物。本申请涉及计划公告PA-09-197：血液系统恶性肿瘤早期检测的生物标记物(R01)。该项目的总体目标是确定可用于朗格汉斯细胞组织细胞增生症(LCH)患者诊断和治疗的新生物标记物。LCH的发生频率与其他罕见的恶性肿瘤相似，包括霍奇金淋巴瘤和AML。然而，与其他肿瘤性白细胞疾病不同的是，人们对LCH的病因知之甚少。由于目前缺乏体外或动物模型，目前的研究依赖于对原生组织的研究。我们在贝勒医学院建立了世界上最大的组织细胞增多症中心，每年有100多例新诊断，使我们能够创建大量的LCH组织和血浆。有了这些宝贵的生物资源和新颖的实验室技术，我们现在能够提出关于LCH的细胞特异性基因表达和细胞起源的基本问题。目前的LCH模型认为，LCH皮损中的病理性朗格汉斯细胞是由于表皮朗格汉斯细胞的恶性转化而产生的。然而，我们对LCH皮损进行的初步细胞特异性基因表达实验发现，病理性朗格汉斯细胞高表达与未成熟髓系细胞相关的基因，并且具有不同于正常表皮朗格汉斯细胞的转录图谱。因此，我们提出假设，LCH是一种起源于骨髓来源的循环髓系树突状细胞(MDCs)的髓系异常增殖症。这一假说将通过以下目标进行检验：具体目标1：确定活动期LCH患者外周血中独特的循环中未成熟的MDC群体，并与疾病风险组相关。特定目的2：确定LCH相关循环未成熟MDCs的基因表达谱，并与疾病风险组相关特定目标3：确定影响活动期LCH患者MDC发育的血浆蛋白，并与疾病风险组相关特定目标4：在小鼠模型中测试LCH候选基因在MDC发育中的作用。 公共卫生相关性：将朗格汉斯细胞组织细胞增生症重新定义为一种髓样发育不良症，并确定用于早期检测和风险评估的生物标志物。该项目的最终目标是确定可用于了解朗格汉斯细胞组织细胞增生症(LCH)的生物学基础的基因、蛋白质和途径，并开发新的策略来诊断、风险分层和治愈LCH患者。这些实验还可能提供对正常人类树突状细胞生物学的洞察，并识别对诊断和治疗其他肿瘤血液系统疾病至关重要的细胞和生物标记物。

DESCRIPTION (provided by applicant): Redefining Langerhans Cell Histiocytosis as a Myeloid Dysplasia and Identifying Biomarkers for Early Detection and Risk Assessment. This application addresses Program Announcement PA-09-197: Biomarkers for Early Detection of Hematopoietic Malignancies (R01). The overall aim of this project is to identify novel biomarkers that may be used to diagnose and treat patients with Langerhans Cell Histiocytosis (LCH). LCH occurs with similar frequency as other rare malignancies including Hodgkin's lymphoma and AML. However, unlike other neoplastic white blood cell disorders, little is known about the etiology of LCH. Due to the current lack of in vitro or animal models, research currently relies on study of primary tissue. We have developed the world's largest Histiocytosis Center at Baylor College of Medicine with over 100 new diagnoses annually, allowing us to create a large bank of LCH tissues and plasma. With these invaluable biological resources and novel lab techniques, we are now able to ask fundamental questions regarding cell-specific gene expression and the cell of origin of LCH. The current model of LCH suggests that pathologic Langerhans cells in LCH lesions arise due to malignant transformation of epidermal Langerhans cells. However, our preliminary cell-specific gene expression experiments from LCH lesions found that pathologic Langerhans cells highly express genes associated with immature myeloid cells and have transcription profiles distinct from normal epidermal Langerhans cells. We therefore propose the hypothesis that LCH is a myeloid dysplasia that arises from bone-marrow derived circulating myeloid dendritic cells (mDCs). This hypothesis will be tested with the following Aims: Specific Aim 1: Identify unique circulating immature mDC populations in peripheral blood from patients with active LCH, and correlate with disease risk groups. Specific Aim 2: Define gene expression profiles of LCH-associated circulating immature mDCs, and correlate with disease risk groups Specific Aim 3: Identify plasma proteins that impact mDC development in patients with active LCH, and correlate with disease risk groups Specific Aim 4: Test the role of LCH candidate genes on mDC development in mouse models. PUBLIC HEALTH RELEVANCE: Redifining Langerhans Cell Histiocytosis as a Myeloid Dysplasia and Identifying Biomarkers for Early Detection and Risk Assessment The ultimate goal of this project is to identify genes, proteins, and pathways that can be used to understand the biological basis of Langerhans Cell Histiocytosis (LCH) and to develop new strategies to diagnose, risk-stratify and cure patients with LCH. These experiments may also provide insight into normal human dendritic cell biology and identify cells and biomarkers important to diagnosis and treatment of other neoplastic hematopoietic diseases.