This application addresses broad Challenge Area (07) Enhancing Clinical Trials and specific Challenge Topic 07-DK-103: Support for Registries Pediatric myelodysplastic syndrome (pMDS) is a rare hematopoietic disease characterized by a heterogeneous group of disorders that include primary or de novo MDS, and """"""""secondary MDS"""""""" following congenital or acquired bone marrow failure (BMF) syndromes or cytotoxic therapy. To date, very little is known about the initiating events leading to pMDS, and thus no targeted therapies exist;bone marrow transplantation is the only therapeutic option for these patients. The heterogeneity in the clinical and laboratory presentation has made it difficult to study pMDS and to identify novel genetic alterations. Limited knowledge of initiating events in childhood MDS have to date prevented a molecular classification with biological relevance. Therefore the disease remains largely classified by morphological and cytogenetic criteria. Unlike MDS in the elderly, certain genetic conditions such as inherited bone marrow failure syndromes, as well as acquired aplastic anemia and MDS in a first-degree relative predispose young patients to MDS. This may provide important insights into the unique features of the pathogenesis of pMDS. In order to be able to study the disease systematically, a large number of samples that are well annotated with a clinical history and ancillary information such as cytogenetics are needed. To date such a large sample collection does not exist within the USA. Therefore, we seek to build a pMDS patient registry and tissue repository that will allow us to gather sufficient patient material to permit systematic and in depth analysis of this family of disorders in the future. A patient registry will provide a platform to improve accuracy of diagnosis for children with MDS by standardized review of morphology and cytogenetics and molecular analysis (for example we seek to utilize the registry to perform whole genome-wide screening approach to identify novel genes involved in pMDS). It will also allow us to evaluate the frequency of the different subtypes of pMDS, as well as assessing survival, relapse rate, morbidity and mortality after HSCT. We have already initiated discussions with the European Working Group of MDS (EWOG-MDS), led by Dr. Charlotte Niemeyer, to learn from their experience setting up a similar registry in Europe that has now been in existence for 10 years. Taken together, we seek to establish a pediatric MDS patient registry in the US that will not only improve the diagnosis by using a standardized approach, but it will also allow us and other future collaborators to perform meaningful translational research on a rare disease for which it is often difficult to collect sufficient numbers of patient samples for analysis. The ultimate hope is that the findings that will emerge from the patient registry will provide new and important insights into the pathogenesis and underlying molecular events that play a role in pMDS, which might lead to future disease-specific therapeutic applications. This project will be lead by Drs. David A. Williams (known for his expertise in hematopoietic stem cells and bone marrow failure disorders) and Mark D. Fleming, (an expert Pediatric Hematopathologist) in collaborative effort, utilizing both their clinical expertise in hematology and marrow failure disorders as well as their expertise in pediatric hematopathology. Drs. Williams and Fleming will be joined in this project by Dr. Inga Hofmann Zhang whose training and background in Pediatric Hematology/Oncology and Hematopathology will provide additional skills to execute the project. This project will be carried out at Children's Hospital Boston, a national leader in pediatric care, and innovation in research and translational medicine. Children's Hospital Boston has a large referral base and is well connected with other centers. This will permit us to expand the referral base to more quickly populate this registry. Furthermore Children's Hospital already has a well-developed infrastructure in clinical Hematology and Hematopathology that will facilitate the execution of this proposal. With the help of funds available through the challenge grants we are confident that with our unique expertise in the fields of hematopoiesis and hematopathology we are well equipped to establish a successful Pediatric MDS patient registry.
Pediatric myelodysplastic syndrome (pMDS) is a rare hematopoietic disease characterized by a heterogeneous group of disorders. To date very little is known about the initiating events leading to pMDS, and thus no targeted therapies exist;bone marrow transplantation is the only therapeutic option for these patients. Our objective is to establish a patient registry and tissue bank that will permit us to reach our overall goal to define the genetics of childhood MDS and identify pathways for therapy, and ultimately translate this knowledge to improve the outcome for these children.
| Keller, Rachel B; Gagne, Katelyn E; Usmani, G Naheed et al. (2012) CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer 59:311-4 |
