Redefining Langerhans Cell Histiocytosis as a Myeloid Dysplasia and Identifying B

描述（由申请人提供）：将朗格汉斯细胞组织细胞增多症重新定义为骨髓增生异常，并确定用于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：用于早期检测造血系统恶性肿瘤的生物标志物（R 01）。该项目的总体目标是确定可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AML）相似。然而，与其他肿瘤性白色血细胞疾病不同，LCH的病因学知之甚少。由于目前缺乏体外或动物模型，研究目前依赖于对原代组织的研究。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例新诊断，使我们能够创建一个大型的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起源细胞的基本问题。目前的LCH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，我们从LCH病变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，并具有不同于正常表皮朗格汉斯细胞的转录谱。因此，我们提出的假设，LCH是一种髓样发育不良，产生于骨髓来源的循环髓样树突状细胞（mDC）。具体目标1：鉴定活动性LCH患者外周血中独特的循环未成熟mDC群，并与疾病风险组相关。具体目标二：定义LCH相关循环未成熟mDC的基因表达谱，并与疾病风险组相关具体目标3：鉴定影响活动性LCH患者mDC发育的血浆蛋白，并与疾病风险组相关具体目标4：在小鼠模型中测试LCH候选基因对mDC发育的作用。

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.