Bone marrow failure (BMF) is characterized by inadequate blood cell production and is often associated with an increased risk of progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia. MDS is most common in older adults, where it is caused by acquisition of somatic mutations that cause hypercellular marrows and ineffective hematopoiesis. By contrast, MDS in children and young adults is more commonly associated with a germline genetic predisposition and hypocellular marrows. However, syndromic features or a clear family history are often absent, so inherited BMF/MDS must be considered in all young patients. The identification of germline genetic predisposition to BMF/MDS is critical as it informs medical management and provides an opportunity for surveillance and early intervention. Fundamental barriers to clinical care of BMF/MDS patients include an incomplete catalogue of causative genes and an inability to accurately predict risk for progression to myeloid malignancy. Therefore, the aims of this study are:
Aim 1) Improve the diagnosis of germline genetic predisposition to BMF/MDS through identification of novel genes and variants in patients for whom targeted sequencing and WES were non-diagnostic, and Aim 2) Identify the somatic genomic, transcriptomic, and epigenomic drivers of disease progression in BMF/MDS with the goal of informing longitudinal management of patients. We will initially focus on Shwachman-Diamond syndrome (SDS) to identify new SDS genes and conduct a longitudinal, integrated analysis of the genomic, molecular, and clinical features of SDS, with the goal of developing an understanding of somatic clonal progression within this well- defined clinical cohort. This approach will then be expanded to include patients with other BMF/MDS disorders in the latter years of the study. This project brings together an integrated team of investigators with expertise in pediatric and adult BMF/MDS, germline genetics, somatic genomics, epigenomics, and transcriptomics. This project leverages ever-growing, pre-existing, annotated repositories of BMF/MDS specimens collected longitudinally from pediatric and adult patients and their family members. Consistent with the mission of the RC2, the clinically annotated datasets generated by these studies will be readily available to the medical and scientific communities through public platforms to promote science, discovery, and clinical care for BMF/MDS in children and young adults.

Public Health Relevance

Bone marrow failure (BMF) leads to low blood cell counts and can be associated with myelodysplastic syndrome (MDS), a pre-leukemic condition. Knowing the specific genetic causes of BMF and the changes associated with progression to leukemia allows physicians to treat or prevent life-threatening medical conditions of BMF/MDS. This grant seeks to expand our understanding of the genes that cause BMF/MDS as well as the acquired changes that occur during progression to leukemia using state-of-the-art gene sequencing and other cutting-edge molecular technologies to inform personally tailored medical management.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
High Impact Research and Research Infrastructure Programs (RC2)
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Special Emphasis Panel (ZDK1)
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Bishop, Terry Rogers
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Boston Children's Hospital
United States
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