Molecular Genetic Investigation of Pediatric Myelodysplastic Syndrome

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DESCRIPTION (provided by applicant): Pediatric Myelodysplastic Syndrome (MDS) is a heterogeneous group of clonal stem cell disorders characterized by varying degrees of cytopenias, and ineffective and dysplastic hematopoiesis. MDS can be classified as primary de novo MDS with no apparent underlying cause and secondary MDS following congenital or acquired bone marrow failure (BMF) disorders or cytotoxic therapies. Little is known about initiating events leading to pediatric MDS. As a result, no targeted therapies exist and hematopoietic stem cell transplantation remains the only therapeutic option. The heterogeneous clinical and laboratory presentation and limited availability of clinically well-annotated patient samples and in vivo models have posed significant obstacles to study the disease and to identify genetic alterations unique to pediatric MDS. Therefore pediatric MDS remains largely classified by morphologic and cytogenetic criteria that provide few clues as to the molecular basis. Over the last 18 months, we have developed the first nationwide comprehensive Pediatric MDS and BMF Disorder Patient Registry and Tissue Repository now involving 3 institutions and continuing to grow. The registry has collected samples from > 60 individual patients in addition to biological material from 3 unique kindreds with pediatric MDS. These samples form the basis for our first genomic sequencing analysis to gather preliminary data for future experiments and represent the power of this registry to elucidate pathogenic mutations associated with MDS. Our unique team of investigators will exploit the registry and catalyze our efforts to determine the fundamental underpinnings of pediatric MDS. The team includes David Williams (clinical/translational hematology), Mark Fleming (pediatric hematopathology /hematological genetics), Benjamin Ebert (high throughput genomic technologies in adult MDS) and Kyriacos Markinanos (genetic linkage analysis). We will undertake preliminary studies to demonstrate feasibility, and generate genomic data that will provide the basis for future hypothesis-driven translational and clinical research studies on a national level. PUBLIC HEALTH RELEVANCE: The underlying genetics and pathophysiology of pediatric MDS is poorly understood. By exploiting several well-characterized families with inherited MDS, we will aim to identify the genetic basis for this disorder. Results obtained not only promise to provide critical insights into the biology of pediatric patients, but will likely increase knowledg into the genetics of adult MDS.