# Mutual reinforcement between somatic mutations and transcription factors in clonal hematopoiesis

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2024 · $422,112

## Abstract

Project Summary/ Abstract
Recent highthroughput exome sequencing has revealed various somatic mutations in individuals with clonal
hematopoiesis (CH) and myelodysplastic syndromes (MDS) patients. Among these mutations, C-to-T
mutations is among the most common type of single mutations observed in CH and MDS. It remains yet to be
explained why C-to-T mutations are preferentially enriched in CH and MDS and how the C-to-T transition alters
hematopoietic stem and progenitor cells (HSPCs) fitness and leads to aberrant clonal expansion. By combining
in vitro biochemical and structural analyses with epigenomic profiling of bone marrow samples from MDS
patients, the team discovered a previously-underappreciated mutual reinforcement between C-to-T transition
and genomic binding of transcription factors (TFs), which contributes to the clonal expansion of HSPCs and
aggravate CH and MDS. In Aim1, the team will use genetically-modified mouse models and CRISPR/Cas9-
based genome editing methods to probe the causality between C-to-T transition and TF binding in HSPCs. In
Aim 2, the team will test how the C-to-T transition and DNA methylation deregulation reshape the genomic
distribution of TFs, subsequently altering downstream transcriptional outputs to cause clonal expansion in
HSPCs. In parallel, the team will use HSPCs purified from CH and MDS patients to further validate findings
made ex vivo and in rodent models. The proposed studies are anticipated to significantly advance our
mechanistic understanding on how TFs shape the genome and how somatic mutations alter transcriptional
regulation in HSPCs. From a translational perspective, discoveries made from this study will lead to the
identification of therapeutic vulnerabilities for CH and MDS treatment.

## Key facts

- **NIH application ID:** 10793498
- **Project number:** 5R01DK132286-02
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Xiaodong Cheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $422,112
- **Award type:** 5
- **Project period:** 2023-03-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793498

## Citation

> US National Institutes of Health, RePORTER application 10793498, Mutual reinforcement between somatic mutations and transcription factors in clonal hematopoiesis (5R01DK132286-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10793498. Licensed CC0.

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