# Functional and molecular basis of ineffective erythropoiesis in SF3B1-mutant myelodysplastic syndromes

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $654,938

## Abstract

SUMMARY
The majority of patients with myelodysplastic syndromes (MDS), a heterogeneous group of blood disorders
characterized by ineffective and clonal hematopoiesis, carry a somatic mutation affecting an RNA splicing
factor. The most commonly mutated splicing factor is SF3B1, a core component of the spliceosome that is
preferentially mutated in MDS with ring sideroblasts (MDS-RS). Although SF3B1 mutations are among the
most common genetic lesions in MDS, they are nonetheless relatively poorly understood. Our incomplete
understanding of SF3B1 mutations is due in part to the absence of a model system that recapitulates hallmark
disease phenotypes, including ring sideroblast formation and ineffective erythropoiesis. As a consequence, it is
unclear how SF3B1 mutations alter RNA splicing mechanisms, which specific mis-spliced genes drive hallmark
disease phenotypes, and whether SF3B1-mutant cells can be killed by targeted therapies.
Here, we propose to elucidate the functional basis as well as mechanistic and phenotypic consequences of
SF3B1 mutations in MDS-RS. Our team consists of a stem cell biologist with expertise in hematologic disease
modeling (Doulatov), a basic scientist with expertise in RNA splicing and functional genomics (Bradley), and a
physician-scientist with expertise in erythropoiesis and heme biology (Abkowitz). In preliminary studies, we
generated MDS-RS patient-derived induced pluripotent stem cells (iPSCs) that recapitulate hallmark disease
phenotypes during erythroid differentiation, identified specific mis-spliced genes that contribute to ineffective
erythropoiesis, and performed functional genomic screens to identify molecular vulnerabilities of SF3B1-mutant
cells. We propose to build on those preliminary studies as follows: Aim 1, Define the molecular consequences
of SF3B1 mutations for mRNA splicing, stability, and translation; Aim 2, Determine the functional basis of ring
sideroblast formation and ineffective erythropoiesis in SF3B1-mutant MDS-RS; Aim 3, Identify therapeutic
opportunities for treating MDS-RS with SF3B1 mutations. The significance of these studies is that they will
elucidate the mechanistic and functional consequences of SF3B1 mutations in MDS-RS. The health
relatedness is that the proposed work may identify new opportunities for treating MDS by specifically targeting
SF3B1-mutant cells. As the incidence of MDS is rising and patients with SF3B1-mutant MDS-RS face life-long
transfusion burdens and associated morbidity and mortality, there is a public health need to develop new
therapies for this disorder.

## Key facts

- **NIH application ID:** 9941945
- **Project number:** 1R01HL151651-01
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Robert K Bradley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $654,938
- **Award type:** 1
- **Project period:** 2020-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941945

## Citation

> US National Institutes of Health, RePORTER application 9941945, Functional and molecular basis of ineffective erythropoiesis in SF3B1-mutant myelodysplastic syndromes (1R01HL151651-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9941945. Licensed CC0.

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