# Systems Biology of Bone Marrow Failure and MDS for Precision Medicine

> **NIH NIH RC2** · BOSTON CHILDREN'S HOSPITAL · 2020 · $1,278,845

## Abstract

Project Summary/Abstract
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.

## Key facts

- **NIH application ID:** 10018490
- **Project number:** 5RC2DK122533-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** MARK D FLEMING
- **Activity code:** RC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,278,845
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018490

## Citation

> US National Institutes of Health, RePORTER application 10018490, Systems Biology of Bone Marrow Failure and MDS for Precision Medicine (5RC2DK122533-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10018490. Licensed CC0.

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