# Insights from somatic genomics lead to novel therapeutic targets in inherited bone marrow failure syndromes: Shwachman-Diamond Syndrome as a model

> **NIH NIH K08** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $168,361

## Abstract

PROJECT SUMMARY/ABSTRACT
Inherited bone marrow failure syndromes are characterized by hematopoietic aplasia and predisposition to
myelodysplasia. These disorders are underdiagnosed, and the only curative treatment is hematopoietic stem
cell transplant. In order to understand the mechanisms that mediate bone marrow failure and clonal evolution,
this proposal focuses on Shwachman-Diamond Syndrome (SDS), a bone marrow failure and MDS predisposition
syndrome caused by biallelic mutations in the SBDS gene. This gene encodes a protein that regulates ribosome
maturation. The SBDS protein specifically promotes formation of the mature, translationally active 80S ribosome
by aiding in catalysis of removal of EIF6 from the 60S ribosomal subunit. Preliminary data presented in this
proposal has identified recurrent and persistent somatic missense mutations in EIF6 and TP53 within the bone
marrow of patients with SDS. The most common EIF6 mutation leads to a loss of function and abolishes EIF6
binding with the 60S ribosomal subunit and improves SDS cell fitness, identifying a novel target for SDS therapy.
The central hypothesis of this proposal is that inherited bone marrow failure syndromes have decreased
hematopoietic cell fitness determined by the inherited molecular defect and somatic mutations specifically rescue
the underlying fitness defect or bypass cell stress pathways. The proposal addresses this hypothesis with the
following specific aims: (1) Identify the hematopoietic cell of origin and hematopoietic consequences of EIF6 and
TP53 somatic mutations in SDS. (2) Evaluate the disruption of the EIF6:60S interaction and decreased EIF6
protein stability in SDS. In the first aim, single cell DNA sequencing combined with DNA-barcoded
immunophenotyping will be used to determine clonal architecture and a single cell genotype-phenotype of
somatic mutations in the SDS bone marrow. In the second aim, rational de novo designed miniproteins will be
used to interrogate EIF6:60S binding as a therapeutic strategy. Data generated from this study will inform the
pathophysiology and treatment of SDS-associated bone marrow failure and can be applied to inform treatment
of other bone marrow failure syndromes, the study of clonal hematopoiesis and ribosome maturation. A K08
award will provide the candidate with protected time to complete additional academic training in computational
biology, somatic genomic analysis and high-throughput proteomics approaches. A detailed career development
plan is proposed which will enable the candidate to attain additional scientific expertise noted above and training
in grant-writing, leadership and management skills. The proposed studies will take place at the Dana-
Farber/Boston Children's Hospital Cancer and Blood disorders center, an exemplary location to acquire
additional training. The candidate has protected research time and strong institutional support. In addition, the
candidate will have access to the Harvard Medical School-af...

## Key facts

- **NIH application ID:** 11033208
- **Project number:** 7K08DK130790-04
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Alyssa Kennedy
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $168,361
- **Award type:** 7
- **Project period:** 2021-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11033208

## Citation

> US National Institutes of Health, RePORTER application 11033208, Insights from somatic genomics lead to novel therapeutic targets in inherited bone marrow failure syndromes: Shwachman-Diamond Syndrome as a model (7K08DK130790-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11033208. Licensed CC0.

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