# Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $569,754

## Abstract

Title: Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations
Abstract
Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by cytopenia and dysplasia
of myeloid linage cells with an increased risk of transformation to acute myeloid leukemia. Current therapies
are inadequate to treat MDS. This underscores a need to better understand the molecular mechanism of MDS
and identify new therapeutic targets in MDS. Mutations in the genes encoding RNA splicing factors (U2AF1,
SRSF2, SF3B1 or ZRSR2) are frequently observed in MDS. U2AF1 is involved in the recognition of the 3’
splice site required for recruitment of the U2 snRNP during pre-mRNA splicing. U2AF1 mutations have been
identified in ~11% cases of MDS. However, the functional roles of U2AF1 mutations in MDS and the
mechanism by which U2AF1 mutations contribute to MDS pathogenesis remain unclear. To determine the
roles of mutant U2AF1 in MDS, we have generated a novel conditional U2AF1-Q157R knock-in mouse. In
preliminary studies, we have observed that hematopoietic expression of U2AF1-Q157R mutant results in a
macrocytic anemia, erythroid dysplasia and expansion of hematopoietic stem cells (HSC) in the bone marrow.
We also have observed that concurrent loss of EZH2 and expression of U2AF1-Q157R mutant promotes rapid
progression of MDS. We hypothesize that U2AF1 mutations trigger RNA splicing alterations, gene expression
changes, DNA damage and replication stress in HSPC leading to aberrant hematopoiesis, and U2AF1
mutations cooperate with epigenetic regulator mutations in the progression of MDS. To test our hypothesis, we
propose three Specific Aims. In Aim 1, we will investigate the consequences of U2AF1-Q157R mutation and
underlying molecular mechanisms in myelodysplasia. In Aim 2, we will determine the biological and molecular
basis for synergy between U2AF1 mutations and co-occurring epigenetic regulator mutations in the
pathogenesis of MDS. In Aim 3, we will identify and test therapeutic strategies for U2AF1 mutant MDS. Results
from these studies will provide new insights into the molecular pathogenesis of MDS and may lead to new
therapeutic approach for treatment of MDS.

## Key facts

- **NIH application ID:** 10866579
- **Project number:** 5R01HL168611-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Golam Mohi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $569,754
- **Award type:** 5
- **Project period:** 2023-06-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866579

## Citation

> US National Institutes of Health, RePORTER application 10866579, Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations (5R01HL168611-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10866579. Licensed CC0.

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