Biomarkers in pediatric versus adult myelodysplastic syndromes

 描述（由申请人提供）：我们计划研究儿童骨髓增生异常综合征（MDS），这是一种以无效造血为特征的血液癌症。MDS在成人中的发病率要高得多，但迫切需要儿科方法来诊断和治疗：表现和临床过程更加异质，疾病病因尚未得到充分研究。预后差，因为进展到晚期疾病和白血病可能迅速发生。移植是唯一的治愈方法，尽管可能发生由于手术相关死亡和疾病复发而导致的治疗失败。替代疗法可用于不适合移植的成年患者，但很少有研究在儿童中进行。为儿童MDS开发新的有效疗法需要更好地了解独特和常见的血液学特征，这可以为疾病的基础机制和推动进展提供重要的见解。我们从国家骨髓捐献者计划（NMDP）和国际血液和骨髓移植研究中心（CIBMTR）获得了129例儿童和100例成人患者样本，沿着人口统计学和MDS病理学详细信息。此外，我们已经从20名成人正常供体中获得了年龄匹配的PBMC对照，目前正在从20名儿童正常供体中获得PBMC。我们将：1）使用FACS分析和建立的表征组评估细胞，所述表征组包括T细胞、B细胞、自然杀伤t（NKT）细胞和自然杀伤（NK）细胞群体、单核细胞亚群、循环CD 34+细胞和免疫调节群体（例如，T调节细胞和髓源性抑制细胞）; 2）检查淋巴细胞和亚群中的免疫调节功能，包括增殖、细胞因子和趋化因子产生、脱粒和细胞毒性。对于免疫调节群体，测量进行共培养测定的抑制功能的能力;以及3）评估临床相关性（例如，年龄、疾病状态、核型、移植结果和巨细胞病毒血清状态）与小儿MDS PBMC表型和功能特征进行比较，并与成人MDS患者进行比较。我们的目标是全面评估和比较儿童和成人MDS方面的细胞类型，功能等，这项工作是更好地了解儿童MDS生物学和开发新的治疗策略的重要一步。

 DESCRIPTION (provided by applicant): We propose to study pediatric myelodysplastic syndromes (MDS), which are blood cancers characterized by ineffective hematopoiesis. MDS has a much higher incidence in adults, but there is an urgent need for a pediatric approach to diagnosis and treatment: the presentation and clinical course is much more heterogeneous and the disease etiology has not been well studied. Prognosis is poor as progression to advanced disease and leukemia can occur rapidly. Transplantation is the only cure, although treatment failure due to procedure-related mortality and disease recurrence can occur. Alternative therapies are available for adult patients ineligible for transplant, but little study has been don in children. Development of new effective therapies for pediatric MDS requires a better understanding of unique and common hematologic features, which could provide important insights into mechanisms that underlie disease and drive progression. We have obtained 129 pediatric and 100 adult patient samples, along with demographic and MDS pathology details, from the National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR). Further, we have obtained age-matched PBMC controls from 20 adult normal donors and are currently obtaining PBMC from 20 pediatric normal donors. We will: 1) evaluate cells using FACS analysis and established characterization panels including T cell, B cell, natural killer t (NKT) cell and natural killer (NK) cell populatios, monocyte subsets, circulating CD34+ cells, and immune-regulatory populations (e.g., T regulatory cells and myeloid derived suppressor cells); 2) examine lymphocyte and immune-regulatory function in subsets including proliferation, cytokine and chemokine production, degranulation and cytotoxicity. For immune-regulatory populations, measure ability to suppress function performing co-culture assays; and 3) Evaluate clinical correlations (e.g., age, disease status, karyotype, transplant outcome and cytomegalovirus sero-status) with pediatric MDS PBMC phenotypic and functional characteristics and compare to adult MDS patients. Our goal is to comprehensively evaluate and compare pediatric and adult MDS with regard to cell type, function, etc. This work is an important step toward better understanding pediatric MDS biology and developing new treatment strategies.