Redefining Langerhans Cell Histiocytosis as a Myeloid Dysplasia and Identifying B

描述（由申请人提供）：重新定义朗格汉斯细胞组织细胞增生症为髓系异常增生，并确定早期检测和风险评估的生物标志物。本申请涉及项目公告PA-09-197：用于早期检测造血恶性肿瘤的生物标志物（R01）。该项目的总体目标是鉴定可能用于诊断和治疗朗格汉斯细胞组织细胞增多症（LCH）患者的新型生物标志物。LCH的发生频率与其他罕见恶性肿瘤（包括霍奇金淋巴瘤和急性髓性白血病）相似。然而，与其他肿瘤性白细胞疾病不同，LCH的病因知之甚少。由于目前缺乏体外或动物模型，目前的研究主要依赖于原代组织的研究。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，每年有超过100个新诊断，使我们能够建立一个大型的LCH组织和血浆库。有了这些宝贵的生物资源和新的实验室技术，我们现在能够提出关于细胞特异性基因表达和LCH细胞起源的基本问题。目前LCH的模型表明LCH病变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，我们在LCH病变中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度表达与未成熟髓样细胞相关的基因，其转录谱与正常表皮朗格汉斯细胞不同。因此，我们提出LCH是骨髓来源的循环骨髓树突状细胞（mDCs）引起的骨髓异常增生的假设。具体目标1：确定活动性LCH患者外周血中独特的循环未成熟mDC群体，并与疾病风险群体相关。特异性目标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。特异性目标3：确定影响活动性LCH患者mDC发展的血浆蛋白，并与疾病风险组相关。特异性目标4：在小鼠模型中测试LCH候选基因对mDC发展的作用。

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.