# Genetic and molecular basis for SRSF2 mutations in myelodysplasia

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $824,642

## Abstract

SUMMARY
Mutations in genes encoding RNA splicing factors are the most common class of genetic alterations in
myelodysplastic syndromes (MDS), a group of blood disorders that are characterized by clonal, dysplastic, and
ineffective hematopoiesis. One of the most commonly mutated genes is SRSF2, which encodes a regulator of
alternative splicing and is subject to recurrent missense mutations primarily affecting a single “hotspot” residue.
During the initial funding period of this grant, work by our labs and others led to a consensus model for how
SRSF2 mutations promote MDS: MDS-associated hotspot SRSF2 mutations alter SRSF2’s RNA-binding
affinity, driving mis-splicing of key hematopoietic regulators to cause dysplastic hematopoiesis. Importantly,
SRSF2 mutations may confer therapeutically actionable vulnerabilities. We identified specific compounds that
modulate RNA splicing to preferentially kill SRSF2-mutant cells over their wild-type counterparts, helping to
motivate the earliest clinical trials of new drugs targeting MDS with splicing factor mutations.
Here, we propose to refine and extend our current understanding of SRSF2 mutations. While useful, our
current model is not sufficient to fully explain the genetic spectrum of SRSF2 mutations, interactions between
SRSF2 mutations and other co-occurring genetic lesions, and the functional roles and therapeutic implications
of SRSF2 mutations in MDS. Our interdisciplinary team consists of a physician-scientist with expertise in MDS
and patient care (Abdel-Wahab) and a basic scientist with expertise in RNA splicing and functional genomics
(Bradley). In preliminary studies, we identified diverse phenomena that are not explained by our current model
of SRSF2 mutations: rare, non-hotspot SRSF2 mutations may be pathogenic; although multiple co-occurring
splicing factor mutations are generally thought to be incompatible with cell survival, a subset of MDS patients
carry two such mutations; SRSF2 mutations cause profound changes in RNA processing beyond mis-splicing
of cassette exons; and SRSF2 mutations induce sensitivity to multiple classes of compounds that modulate
RNA splicing via distinct mechanisms of action. We propose to build on these preliminary studies as follows:
Aim 1, Determine the molecular basis and functional consequences of widespread intron retention in SRSF2-
mutant MDS; Aim 2, Determine the biological and molecular basis for allele-specific interactions between
SRSF2 mutations and additional genetic alterations in MDS; Aim 3, Identify and test therapeutic strategies for
targeting cells with spliceosomal gene mutations. The significance of these studies is that they will give insight
into the molecular and functional basis for SRSF2 mutations in MDS. The health relatedness of this effort is
that the proposed work may identify new treatment modalities that specifically target SRSF2-mutant MDS,
which is associated with particularly poor prognosis.

## Key facts

- **NIH application ID:** 10051156
- **Project number:** 2R01HL128239-06
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Omar Abdel-Wahab
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $824,642
- **Award type:** 2
- **Project period:** 2015-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051156

## Citation

> US National Institutes of Health, RePORTER application 10051156, Genetic and molecular basis for SRSF2 mutations in myelodysplasia (2R01HL128239-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10051156. Licensed CC0.

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