DDX6 undergoes phase separation to modulate metabolic plasticity and chemoresistance
Stress granules (SGs) and processing bodies (PBs), assembled via liquid-liquid phase separation (LLPS), are critical for spatial regulation of gene expression in the cytoplasm. However, their roles in tumorigenesis remain poorly understood. Here, we show DEAD-box helicase 6 (DDX6) as the most promising vulnerability in acute myeloid leukemia (AML) through in vitro and in vivo CRISPR screenings using a specialized library targeting RNA-binding proteins enriched in SGs and PBs. Knockout (KO) of DDX6 significantly delays leukemogenesis with minimal impact on normal hematopoiesis. Importantly, the functions of DDX6 in AML depend largely on its ability to trigger LLPS and PB assembly. Mechanistically, PBs serve as "reservoirs" for the mRNAs interacting directly with DDX6 and having low GC content. DDX6 KO leads to rapid PB dissolution and release of PB-enriched mRNAs, such as BCAT1, into the cytosol, where these transcripts undergo degradation. By reducing BCAT1 levels, DDX6 KO reprograms amino acid metabolism and sensitizes AML cells to cytarabine chemotherapy.
Authors
- James C. Mulloy (ORCID: https://orcid.org/0009-0006-6265-938X)
- Lu Yang (ORCID: https://orcid.org/0000-0001-7952-0399)
- Xiwei Wu
- Steven T. Rosen (ORCID: https://orcid.org/0000-0002-8818-7724)
- Mark Wunderlich (ORCID: https://orcid.org/0000-0002-2166-5146)
- Meilin Xue (ORCID: https://orcid.org/0009-0000-8927-3678)
- Lili Ren (ORCID: https://orcid.org/0000-0003-2623-0579)
- Hongjie Bi (ORCID: https://orcid.org/0000-0001-6747-4022)
- H. Zhang (ORCID: https://orcid.org/0000-0001-6878-8584)
- Johanna ten Hoeve-Scott
- Hanjun Qin (ORCID: https://orcid.org/0000-0002-0370-0913)
- Chun‐Wei Chen (ORCID: https://orcid.org/0000-0002-8737-6830)
- Lei Dong (ORCID: https://orcid.org/0000-0001-9574-0148)
- Xueer Wang
- Wei Li (ORCID: https://orcid.org/0000-0003-0672-7473)
- Zheng‐Xiang Li (ORCID: https://orcid.org/0000-0003-4350-5976)
- Xiaoxu Zhang (ORCID: https://orcid.org/0000-0003-0361-5556)
- Bin Zhang (ORCID: https://orcid.org/0000-0003-4703-7524)
- Jianjun Chen (ORCID: https://orcid.org/0000-0003-3749-2902)
- Ling Li (ORCID: https://orcid.org/0000-0001-7568-939X)
- Rui Su (ORCID: https://orcid.org/0000-0002-4807-6229)
- Anthony W.H. Chan (ORCID: https://orcid.org/0000-0002-1771-163X)
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- City Of Hope National Medical Center (US)
- Mayo Clinic (US)
- Harbin Medical University (CN)
- University of California, Los Angeles (US)
- UCLA Medical Center (US)
- City of Hope (US)
- Mayo Clinic in Arizona (US)
- Mayo Clinic in Florida (US)
- Beckman Research Institute
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-02
- DOI
- https://doi.org/10.1038/s41467-025-66966-4
- Citations
- 1
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Institutes of Health