# The Role of DDX41 in Inherited Myelodysplastic Syndromes

> **NIH NIH K01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $150,444

## Abstract

Project Summary
Myelodysplastic syndromes (MDS) are genetic disorders caused by impaired hematopoietic stem/progenitor
cells (HSPC), which can transform to acute myeloid leukemia (AML). MDS typically occurs in the ageing
population, however MDS can also manifest as a result of inherited germline mutations in younger individuals.
Mutations in the DEAD/H-box helicase gene DDX41 are among the most common alterations associated with
inherited MDS. Inherited DDX41 mutations are heterozygous and are typically frameshifts, suggesting that
these mutations result in loss of DDX41 function. DDX41 mutations are also observed in de novo MDS and
AML, and are typically missense mutations frequently resulting in the amino acid substitution R525H. DDX41 is
an RNA helicase that hydrolyzes ATP, and can function as an innate immune sensor, RNA splicing factor, and
ribosome regulator. The precise mechanism(s) by which DDX41 mutations alter HSPC function and contribute
to MDS/AML remains unknown. As such, the proposed project will define the role of DDX41 mutations in the
pathogenesis of MDS/AML. To mimic the frameshift mutations observed in human MDS and determine the role
of DDX41 in normal hematopoiesis, we generated hematopoietic-specific and conditional Ddx41-deficient
mice. Our preliminary data has revealed that DDX41-deficiency (complete knockout) is not compatible with
HSPC function and hematopoiesis, whereas DDX41 heterozygosity increases BM HPSC. In addition, through
integrative proteomic and biochemical approaches we identified a novel DDX41-interacting protein in leukemic
cells, SAMHD1, a dNTPase and host defense factor, which controls cellular pools of dNTPs. Collectively, our
preliminary data indicate that DDX41 has a critical role in hematopoiesis and HSPC function. We hypothesize
that diminished DDX41 expression and/or function contributes to ineffective hematopoiesis and to the
pathogenesis of MDS and AML, in part due to increased SAMHD1 activity and altered cellular dNTP pools.
Therefore, the objectives of this proposal are to model somatic and germline DDX41 mutations in normal and
malignant hematopoiesis, and to elucidate the molecular function of DDX41 required for HSPC function.
Through extensive hematopoietic approaches, we will define the role of DDX41 deficiency and R525H
expression in MDS incidence and progression to AML (Aim 1). Since DNMT3A and DDX41 mutations
commonly co-occur in MDS patients that have progressed to AML, we will determine whether DDX41
heterozygosity or R525H expression combined with DNMT3A-deficient mice will result in high-risk MDS or
overt AML. Reduced cellular dNTP pools impair cell cycle progression and result in genomic instability;
therefore, we will determine the role of SAMHD1 activity in DDX41-deficient HSPC or mutant MDS, and
whether diminished cellular dNTPs pools lead to genomic instability and development of AML (Aim 2). By
elucidating the function of DDX41 malignant hematopoiesis, we predict to uncover nove...

## Key facts

- **NIH application ID:** 9971526
- **Project number:** 5K01DK121733-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Timothy Michael Chlon
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $150,444
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971526

## Citation

> US National Institutes of Health, RePORTER application 9971526, The Role of DDX41 in Inherited Myelodysplastic Syndromes (5K01DK121733-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971526. Licensed CC0.

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