August 2025

ONCOLOGY

HOW A ‘DNA DETANGLER’ GENE PROTECTS AGAINST BLOOD CANCER

Featuring: ​Peng Ji, MD, PhD, ‘15 GME

A new Northwestern Medicine study has revealed how a common inherited mutation disrupts red blood cell development and sparks inflammation that can lead to leukemia, according to findings published in Nature Communications.

Scientists have uncovered how mutations in a gene called DDX41 — one of the most common inherited risk factors for bone marrow cancers — derail red blood cell production and can trigger a dangerous inflammatory response that may lead to blood cancers like myelodysplastic syndrome and acute myeloid leukemia.

The study, led by Peng Ji, MD, PhD, ‘15 GME, the Marie A. Fleming Research Professor of Pathology in the Divisions of Experimental Pathology and Hematopathology, sheds light on a long-standing mystery: how DDX41 normally functions in healthy cells and why its loss is so damaging.

“We noticed that many patients with faulty DDX41 often develop anemia,” said Ji, who is also vice chair for research in the Department of Pathology. “That led us to suspect that red blood cell development might be especially vulnerable to the loss of this gene.”

In the study, Ji and his collaborators deleted DDX41 in mice and in cultured cells.

In mice, deleting DDX41 during early red blood cell development proved fatal. However, removing it later or in other blood cell types had minimal effects, highlighting the gene’s unique importance in the process of forming red blood cells.

​The team also used lab-grown bone marrow “mini-organs” derived from patient stem cells to confirm their findings in human tissue.

By comparing mini-organs with and without mutations, Ji and his collaborators observed that DDX41 plays a critical role in maintaining the integrity of DNA in red blood precursor cells. Specifically, it acts as a “DNA detangler,” resolving complex DNA structures known as G-quadruplexes (G4s) — 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.”

That alarm system is the cGAS-STING pathway, a molecular danger signal that responds to DNA damage by jumpstarting inflammation. In the absence of DDX41, this pathway becomes hyperactive, leading to the death of immature red blood cells and, eventually, 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 said.

Now, the investigators plan to test existing drugs that block the cGAS-STING pathway in animal models, with the hope of eventually preventing red blood cell loss in patients with DDX41 mutations. They also aim to explore whether similar DNA-knot stress contributes to other blood disorders, Ji said.

“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.”

​Honghao Bi, a postdoctoral fellow in the Ji laboratory, was first author of the study.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Disease grant R01-DK124220, National Heart, Lung, and Blood Institute (NHLBI) grant R01-HL148012, R01-HL150729, R01-HL169507 and R35-HL171168. Additional funding was provided by National Cancer Institute grant R00-CA248835, as well as the F32 Ruth L. Kirschstein Postdoctoral Individual National Research Service Award (F32-HL170648), the NIH K99 pathway to independent award (K99CA289959) and the EvansMDS foundation Young Investigator award. 

​This article was originally published in the Feinberg School of Medicine News Center on August 20, 2025. 
Peng Ji, MD, PhD, ‘15 GME, the Marie A. Fleming Research Professor of Pathology in the Divisions of Experimental Pathology and Hematopathology, was senior author of the study.
Honghao Bi, a postdoctoral fellow in the Ji laboratory, was first author of the study.

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