Translational Studies of Inherited Marrow Failure and Myelodysplastic Syndromes

描述(申请人提供)：遗传性骨髓衰竭和骨髓增生异常综合征(iBMF/MDS)是一组不同类型的疾病，其特征是造血功能受损并有发展为白血病的倾向。尽管这一领域最近取得了进展，但相当大比例的遗传性骨髓衰竭或MDS患者并不属于已知的诊断类别，仍然是特发性的。由于这些遗传综合征中的许多需要特殊的处理和治疗考虑，与用于获得性骨髓衰竭/MDS的标准疗法显著不同，准确的诊断是至关重要的。这是一项资源开发和基因发现基金，旨在研究iBMF/MDS的表型谱，开发新的骨髓病理成像方法，并深入了解调节造血和骨髓衰竭的遗传和分子机制。我们将应用先进的基因组学方法，从全面表型的儿童和成人样本中识别与iBMF/MDS有关的新基因。该项目还将调查iBMF/MDS中体细胞获得性基因突变对疾病进展和预后的临床和生物学后果，并确定遗传性和获得性骨髓衰竭/MDS之间的遗传格局的相似或不同。我们还将询问在普通人群中出现的看似零星的骨髓衰竭或MDS，以寻找遗传性疾病的隐匿表现。为更广泛的临床和科学界产生的资源将包括用于iBMF/MDS的高通量多路基因分析平台、用于iBMF/MDS诊断工作和管理的循证算法、集中的血液病理学审查，以及用于进一步研究的全面的临床注释生物样本。该项目将对血细胞发育和骨髓衰竭和MDS的分子发病机制产生新的见解；将推动骨髓衰竭和MDS的新诊断测试、治疗和生物标志物的开发；将为血液学界提供临床资源；将为未来调控造血的分子途径的研究提供新的工具和方法。

DESCRIPTION (provided by applicant): The inherited bone marrow failure and myelodysplastic syndromes (iBMF/MDS) are a heterogeneous group of disorders that are characterized by impaired hematopoiesis and a propensity to progress to leukemia. Despite recent advances in the field, a significant percentage of patients presenting with inherited marrow failure or MDS do not fall into the known diagnostic categories and remain idiopathic. Since many of these genetic syndromes entail specific management and treatment considerations that differ significantly from standard therapies used for acquired marrow failure/MDS, accurate diagnosis is essential. This is a resource development and gene discovery grant investigating iBMF/MDS to characterize their phenotypic spectrum, to develop novel imaging modalities for bone marrow pathology, and to gain insights into the genetic and molecular mechanisms regulating hematopoiesis and marrow failure. We will apply cutting edge genomics approaches to samples from comprehensively phenotyped children and adults to identify new genes responsible for iBMF/MDS. This project will also investigate the clinical and biological consequences of somatically acquired genetic mutations on disease progression and prognosis in iBMF/MDS and determine the similarities or differences in genetic landscapes between inherited versus acquired marrow failure/MDS. We will also interrogate seemingly sporadic marrow failure or MDS presenting in the general population for cryptic presentations of inherited disorders. Resources generated for the broader clinical and scientific communities will include high-throughput multiplexed gene analysis platforms for iBMF/MDS, evidence- based algorithms for the diagnostic workup and management of iBMF/MDS, centralized hematopathology review, and comprehensively clinically annotated biological samples for further investigation. This project should yield new insights into blood cell development and the molecular pathogenesis of marrow failure and MDS; will advance the development of new diagnostic tests, therapies and biomarkers for marrow failure and MDS; will provide clinical resources forthe hematology community; and will provide new tools and methods for future studies ofthe molecular pathways regulating hematopoiesis.