# Advanced Mouse Models of DDX41-mutated Myelodysplastic Syndromes

> **NIH NIH R03** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $120,375

## Abstract

Project Summary
Myelodysplastic Syndromes (MDS) are blood disorders caused by defective hematopoietic stem cells (HSC) that
clonally expand and fail to produce blood cells of sufficient quality and quantity. Germline heterozygous
mutations in DDX41, an essential RNA Helicase, are the most common cause of inherited predisposition to MDS.
These mutations are typically frameshifts and cause loss of full-length protein. Patients with these mutations
have normal health into adulthood but have an elevated risk of developing MDS with a median age of 69 years.
The cellular and molecular mechanisms by which these mutations contribute to MDS pathogenesis remain poorly
defined. The most common co-mutation in these patients is acquired missense mutation of the other DDX41
allele, often causing the amino acid substitution R525H. We developed two conditional mutant Ddx41 alleles to
model the germline loss-of-expression mutation and the acquired R525H mutation in mice. We found that mice
with hematopoietic-specific, heterozygous loss of Ddx41 live normal length lives and have predominantly normal
hematopoiesis with only a modest reduction in red blood cell number. In contrast, the combination of one loss-
of-expression allele and the R525H-mutant allele causes profound cell cycle arrest and apoptosis in proliferative
hematopoietic progenitor cells. This observation calls into question why the R525H mutation arises and how the
mutant clones that acquire it can expand to contribute to disease. In patients, the acquired mutation has a median
variant allele frequency of just 10%, indicating it occurs in a non-dominant clone, consistent with reduced
proliferative capacity. In this project, we plan to develop models of DDX41-mutated MDS that account for the
cellular and temporal context of mutation acquisition, including DDX41-heterozygosity in hematopoietic and non-
hematopoietic cells during natural aging and the acquisition of the R525H mutation in only a subset of HSC at
an advanced age. To do this, we will age large cohorts of constitutive Ddx41+/- mice and Ddx41+/flox;Vav-Cre
(hematopoietic-specific) mice to at least 24 months of age. We will also cross these models with a genetic model
of accelerated aging to drive more rapid disease development. Finally, we will induce expression of the R525H
mutation in a subset of HSC in the context of Ddx41+/- bone marrow to mimic the mixed clonality of MDS patient
bone marrow. We hypothesize that these genetic models, which accurately follow the natural progression of the
disease in vivo, will yield MDS-like disease states that can be further studied to elucidate the cellular and
molecular mechanisms of MDS pathogenesis. The ultimate goal of these studies is to fully understand the cause
of MDS predisposition in patients with DDX41 mutations such that we can rationally design strategies to prevent
or treat the disease.

## Key facts

- **NIH application ID:** 10946759
- **Project number:** 1R03DK140185-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Timothy Michael Chlon
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $120,375
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10946759

## Citation

> US National Institutes of Health, RePORTER application 10946759, Advanced Mouse Models of DDX41-mutated Myelodysplastic Syndromes (1R03DK140185-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10946759. Licensed CC0.

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