# Biologic and Therapeutic Consequences of Distinct Hotspot SF3B1 Mutations in MDS

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $409,375

## Abstract

Project Summary
The myelodysplastic syndromes (MDS) are the most common clonal blood disorders, characterized by
dominance of the bone marrow by abnormal stem cells and impairment of blood cell production. Patients with
MDS suffer from combinations of anemia, infection, bleeding, and multiorgan failure from progressive disease.
Outcomes are poor, and treatments are inadequate. Key to developing new treatments is better understanding
of the mutations which create these diseases. Roughly half of MDS patients have mutations in spliceosome
genes, and of these, SF3B1 is the most commonly mutated. Mutant SF3B1 is neomorphic, disrupting RNA
splicing to create what we refer to as JEMs (splice Junctions Enriched in Mutant-spliceosome cells), though how
JEMs produce MDS phenotypes is unknown. SF3B1 mutation is regarded as a favorable prognostic marker in
MDS. Yet, there is considerable heterogeneity in the pathologic features and clinical outcomes of SF3B1-mutant
MDS that remains unexplained. As this heterogeneity beguiles effective disease management, its causes need
to be better understood. The premise of our proposal is that a key to understanding SF3B1-mutant MDS is to
study the differences between distinct SF3B1 mutations. This gene is mutated in hotspots affecting multiple
amino acids, and our preliminary data show that specific mutations associate with distinct clinical features, RNA
splicing patterns, and responses to therapy. We also have data that SF3B1 mutations disrupt metabolism in
specific ways that likely affect sideroblastic anemia and metabolic vulnerabilities, and we have developed novel
human models of SF3B1-mutant hematopoiesis with which to study these processes. The proposed work
combines the expertise of a physician-scientist (Dr. Dalton) who specializes in cell biology, genetics, and human
cell modeling of disease with that of a clinical investigator (Dr. DeZern) who specializes in clinical studies of bone
marrow failure disorders. Together, we will pursue three aims: 1) Characterize the landscape of private and
shared JEMs among hotspot SF3B1 mutations in MDS. We will use RNA-seq of primary MDS samples and
isogenic human cell models to map the RNA splicing landscape of different SF3B1 mutations and use this as a
‘way in’ to understanding the pathways they disrupt. 2) Establish the role of distinct SF3B1 mutations in the
growth and differentiation of human hematopoietic cells. We will use primary MDS samples and isogenic cells to
determine mechanisms of sideroblastic anemia, cell fitness, and metabolic vulnerability in SF3B1-mutant
hematopoietic cells. 3) Define the clinicopathologic features of distinct SF3B1 mutations in MDS. Leveraging the
high-quality data from the NHLBI National MDS Study, we will determine how distinct hotspot SF3B1 mutations
affect pathologic and clinical features of MDS through multivariate analysis. Successful completion of these aims
promises to reveal pathophysiologic mechanisms of RNA splicing, redefine ...

## Key facts

- **NIH application ID:** 10446728
- **Project number:** 1R01HL159306-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** AMY E DEZERN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,375
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446728

## Citation

> US National Institutes of Health, RePORTER application 10446728, Biologic and Therapeutic Consequences of Distinct Hotspot SF3B1 Mutations in MDS (1R01HL159306-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10446728. Licensed CC0.

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