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New research has revealed how a common inherited mutation in the DDX41 gene – one of the most common genetic risk factors for bone marrow cancers – can disrupt red blood cell development and activate inflammatory responses that may drive progression to leukemia.
The research is published in Nature Communications.
Red blood cell precursors are highly sensitive to DDX41 loss
The research set out to shed light on a long-standing mystery: how DDX41 normally functions in healthy cells and why its loss can be so damaging.
“We noticed that many patients with faulty DDX41 often develop anemia,” explained senior author Peng Ji, MD, PhD, the Marie A. Fleming research professor of pathology in Northwestern University’s Feinberg School of Medicine. “That led us to suspect that red blood cell development might be especially vulnerable to the loss of this gene.”
In the study, researchers deleted DDX41 in mouse models and cell cultures to examine its role in blood cell development. Loss of the gene during early red blood cell formation was found to be fatal in mice, while deletion in other blood cell types or later stages of development had limited effects. This suggests that DDX41 is particularly critical during the early stages of red blood cell formation.
DNA damage initiates inflammatory cell death
To validate their findings in human tissue, the team created bone marrow organoids from patient-derived stem cells that either contained no mutations or DDX41 mutations. Organoids with DDX41 mutations showed disrupted red blood cell development and elevated levels of DNA damage.
From this, the researchers concluded that DDX41 acts as type of “DNA detangler”, playing a critical role in maintaining the integrity of DNA in red blood precursor cells. Specifically, it helps resolve complex DNA structures known as G-quadruplexes – knot-like formations that can interfere with DNA replication and gene expression if left unresolved.
“Red blood cell genes are rich in these DNA knots,” said Ji, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “We found that DDX41 binds to and unwinds them. When it’s mutated, these knots accumulate, causing DNA damage and triggering a cellular alarm system.”
When DDX41 is mutated or absent, unresolved G-quadruplexes build up, leading to DNA damage. This damage triggers the cGAS-STING pathway, a key immune surveillance mechanism that responds to the presence of cytosolic DNA by initiating inflammation. Persistent activation of this pathway in red blood cell precursors results in their destruction, ultimately leading to anemia.
“Collectively, the study positions DDX41 as a guardian of red blood cell precursors and traces how its failure sparks cGAS-STING–driven inflammation that progresses from anemia to blood cancer,” Ji explained.
Implications for treatment
Researchers are now testing whether blocking the cGAS-STING pathway in animal models could prevent red blood cell loss in individuals with DDX41 mutations. They also aim to investigate whether G-quadruplex accumulation contributes to other hematological diseases.
“We’re elevating G-quadruplexes from biochemical curiosities to real drug targets,” Ji said. “DDX41 is the cell’s DNA detangler for building red blood cells. When it’s absent, knots accumulate, trigger an inflammatory kill-switch, and lead to anemia — a chain reaction we believe can be halted by drugs that either block the switch or help untangle the knots.”
Reference: Bi H, Ren K, Wang P, et al. DDX41 resolves G-quadruplexes to maintain erythroid genome integrity and prevent cGAS-mediated cell death. Nat Commun. 2025;16(1):7195. doi: 10.1038/s41467-025-62307-7
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