# Synergestic roles of SRF2 and RUNX1 in blood cell development and pathology

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $620,251

## Abstract

Summary
Myelodysplastic Syndromes (MDS) are chronic hematopoietic disorders characterized by dysplasia, inefficient
hematopoiesis, and the propensity to transform into acute myeloid leukemia (AML). Recent advances in
genomic sequencing revealed a large number of mutations associated with the disease, which can be roughly
grouped into three classes: (1) genes involved in signaling (i.e. FLT3, JAK2, KRAS), (2) genes functioning at
the levels of chromatin and pre-mRNA splicing (i.e. RUNX1, ASXL1, SRSF2, U2AF1), and (3) genes
responsible for establishing/maintaining the genome methylome (i.e. DNMT3a, TET2, IDH1/2). Given MDS is
highly heterogeneous in its clinical features, a fundamental question is whether individual mutations cause the
disease via distinct mechanisms or whether many mutations function in some converging pathways. Support of
the latter possibility is the co-occurrence of many of these causal mutations in MDS patients.
As disease-oriented (Zhang) and mechanism-central (Fu) labs, we have been taking advantage of our
combined expertise to work together under this funded R01 to attack some pressing questions in the field,
focusing on RUNX1 and SRSF2. In the past funding cycle (9/2013-present), we have made two conceptual
breakthroughs. First, by linking specific mutations to splicing responses in MDS patients, we found that non-
overlapping responses induced by splicing factor mutations are converged to the common pathways of cell
cycle and DNA damage response. Second, we unexpectedly uncovered that, besides their traditional roles in
splicing, all causal mutations in key splicing factors trigger excessive R-loop formation, leading to replication
stress and cell cycle checkpoint activation. These findings point to dysregulation of the DNA damage response
as a common ground for MDS etiology. Importantly, such elucidated common ground has laid a critical
foundation for our next phase of investigation, which is to understand the contribution of individual mutations to
MDS and potential synergy among them, despite their diverse roles in regulating gene expression. Building
upon both our published and unpublished results, we propose to pursue the following specific aims in the next
phase: Aim 1. Function of RUNX1 and its synergy with SRSF2 in preventing DNA damage; Aim 2. Mutant
SRSF2 and epigenetic regulators to synergistically drive aberrant gene expression; Aim 3. Potential
mechanism for bypassing R-loop-induced cell cycle checkpoint activation.

## Key facts

- **NIH application ID:** 10400021
- **Project number:** 5R01DK098808-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** DONG-ER ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $620,251
- **Award type:** 5
- **Project period:** 2013-09-16 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400021

## Citation

> US National Institutes of Health, RePORTER application 10400021, Synergestic roles of SRF2 and RUNX1 in blood cell development and pathology (5R01DK098808-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10400021. Licensed CC0.

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