# Mutant p53 in pathogenesis of Myelodysplastic Syndromes

> **NIH NIH F31** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $41,596

## Abstract

PROJECT SUMMARY
Human aging is associated with an exponential increase in the occurrence of clonal hematopoiesis of
indeterminate potential (CHIP), which is associated with an increased risk of hematologic neoplasms such as
myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Somatic mutations in the tumor
suppressor gene TP53 rank in the top five among genes mutated in CHIP. TP53 mutations are found in 10 to
15% of MDS patients and are associated with poor prognosis. We found that TP53 mutations identified in
CHIP and MDS promote HSPC expansion and drive MDS pathogenesis during aging. However, the underlying
mechanisms are largely unknown. Dysregulated pre-mRNA splicing has been implicated in human aging and
MDS. Mutations in splicing factors are frequently found in CHIP and MDS. We found that mutant p53 alters
pre-mRNA splicing in key regulators of inflammatory response during aging. Further, we found that mutant p53
cooperates with splicing factor mutations in pathogenesis of hematological malignancies. We hypothesize that
mutant p53 drives the pathogenesis of MDS through altering pre-mRNA splicing in hematopoietic stem and
progenitor cells (HSPCs) during aging. In this proposed research, we will utilize biochemical, genetic,
molecular, and pharmacological approaches as well as vertebrate models to investigate the mechanisms by
which mutant p53 drives MDS pathogenesis. We will determine the sensitivity of human MDS cells with TP53
mutations to spliceosome inhibitor treatment. Delineating the impact of dysregulated pre-mRNA splicing on
aged HSPCs will fill a significant knowledge gap regarding the mechanisms by which TP53 mutations promote
CHIP progression and drive MDS pathogenesis. The proposed research is highly significant because we will
interrogate the role of the spliceosome as a novel potential target for treating MDS patients with TP53
mutations.

## Key facts

- **NIH application ID:** 10313142
- **Project number:** 1F31HL160120-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Sergio Barajas
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $41,596
- **Award type:** 1
- **Project period:** 2022-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313142

## Citation

> US National Institutes of Health, RePORTER application 10313142, Mutant p53 in pathogenesis of Myelodysplastic Syndromes (1F31HL160120-01). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/10313142. Licensed CC0.

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