# Uncovering the Role of the DEAD Box Helicase Ddx41 in Hematopoiesis

> **NIH NIH F30** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $51,036

## Abstract

Abstract
Myelodysplastic syndromes (MDS), a group of pre-malignant bone marrow failure syndromes arising from
defects in hematopoietic stem cells (HSCs), are amongst the most common hematological malignancies of the
elderly with ~30% progressing to acute myeloid leukemia (AML). Recently, loss-of-function germline and
somatic mutations in the DEAD-box Helicase 41 gene (DDX41) have been identified in patients with MDS and
AML, and are thought to contribute to disease pathogenesis. Both germline and somatic DDX41 mutations are
thought to promote hematopoietic deregulation and leukemogenesis. Although a strong clinical correlation is
found between mutations in DDX41 and MDS, the in vivo role of DDX41 in hematopoiesis has not been
elucidated. To address this question, we will characterize hematopoiesis in a zebrafish ddx41 loss-of-function
mutant. Our preliminary studies indicate that ddx41 mutants develop neutropenia and anemia. This animal
model will allow us to elucidate the in vivo role of Ddx41 in normal hematopoiesis and the underlying
mechanism for any defects. DDX41 has been implicated in splicing and shown to associate with components
of the spliceosome including Splicing Factor 3B, subunit 1 (SF3B1), the most commonly mutated splicing factor
in MDS. Additionally, MDS/AML patient samples with DDX41 mutations displayed errors in mRNA splicing that
typically occur when components of the spliceosome are defective. Although these data point towards a role
for DDX41 in splicing, it is still unknown if splicing aberrations contribute to the observed abnormalities in
DDX41-mutated hematologic diseases. Using ddx41-deficient zebrafish will permit us to delineate the
functionally relevant early molecular events leading to blood cell defects when ddx41 is mutated, which is
anticipated to provide novel insight into the origins of MDS. In this proposal, we will use our novel in vivo
model of Ddx41-deficiency to test the hypothesis that Ddx41 is critical for normal hematopoiesis via regulation
of splicing, and that malfunctioning of this process contributes to the hematological defects seen in DDX41-
mutated MDS/AML. In Aim 1, we will determine which blood populations require Ddx41 and which functional
domains of Ddx41 are required for healthy hematopoiesis. In Aim 2, we will elucidate connections between
DDX41 and SF3B1 using protein and genetic interaction studies. Combined these studies will reveal insights
into the pathophysiology of DDX41-mutated MDS/AML.

## Key facts

- **NIH application ID:** 10212445
- **Project number:** 5F30HL142161-05
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Joshua Weinreb
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2018-07-16 → 2022-07-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212445

## Citation

> US National Institutes of Health, RePORTER application 10212445, Uncovering the Role of the DEAD Box Helicase Ddx41 in Hematopoiesis (5F30HL142161-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212445. Licensed CC0.

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