# Targeting splicing in myelodysplasia through GSK-3

> **NIH NIH R56** · UNIVERSITY OF PENNSYLVANIA · 2022 · $99,999

## Abstract

(PLEASE KEEP IN WORD, DO NOT PDF)
Recurrent mutations in the splicing factors SRSF2 and SF3B1 are common in myelodysplasia
(MDS). These gain of function mutations are mutually exclusive and invariably heterozygous,
indicating that cells with splicing factor mutations require some wild-type splicing activity to
survive. Further perturbation of the splicing apparatus is lethal, creating a therapeutic vulnerability
for splicing factor mutant neoplasms. Thus, small molecule splicing inhibitors are currently being
explored to treat splicing factor mutant MDS, but they have had intolerable side effects and
limited efficacy so far, indicating that new approaches to inhibit splicing are needed. We found
that the signaling protein glycogen synthase kinase-3 (GSK-3) phosphorylates multiple splicing
factors and regulates the alternative splicing of a broad range of mRNAs. Inhibition of GSK-3
disrupts splicing and promotes cell death selectively in hematopoietic cell lines with heterozygous
mutations in SRSF2 or SF3B1. Our long-term goals are to define the role of GSK-3 as a
novel, global regulator of splicing and to test whether GSK-3 inhibitors are selectively
lethal in vivo for MDS cells with splicing factor mutations. Our preliminary data support this
hypothesis in hematopoietic cell lines, but it is important to establish these findings in primary
human cells from patients with MDS and CMML. We will express SRSF2wt or the pathogenic
SRSF2P95H mutation in primary cells from patients with MDS to ask whether expression of the
pathogenic mutation confers sensitivity to GSK-3 inhibition in an otherwise isogenic context.
These experiments will provide critical preliminary data and lay the groundwork for future
experiments to investigate the role of GSK-3 as a global regulator of splicing and as a potential
therapeutic target in splicing factor mutant MDS.

## Key facts

- **NIH application ID:** 10677505
- **Project number:** 1R56DK133258-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** PETER S KLEIN
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $99,999
- **Award type:** 1
- **Project period:** 2022-09-16 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10677505

## Citation

> US National Institutes of Health, RePORTER application 10677505, Targeting splicing in myelodysplasia through GSK-3 (1R56DK133258-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10677505. Licensed CC0.

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