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CHRNB4-Mediated Neuroactive Signaling Rewiring Drives Adaptive Resistance to BCL-2 Inhibition in Acute Myeloid
Hiroaki Koyama1,2, Sachiko Seo2, William Tse1,3
1Department of Medicine, The MetroHealth System, Case Western Reserve University, 2500 Metro Health Drive, Cleveland, OH 44109, USA.
Cancers
|May 4, 2026
Summary
Drug resistance to venetoclax in acute myeloid leukemia (AML) is a major challenge. We found the neuroactive ligand-receptor interaction pathway and CHRNB4 downregulation drive this resistance, offering new therapeutic targets.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Venetoclax (BCL-2 inhibitor) efficacy in acute myeloid leukemia (AML) is limited by frequent drug resistance.
- Understanding the molecular mechanisms of venetoclax resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the molecular landscape of venetoclax resistance in AML.
- To identify novel therapeutic targets for overcoming venetoclax resistance.
Main Methods:
- Development of venetoclax-resistant AML cell models.
- Transcriptomic profiling and KEGG pathway analysis.
- In vitro and in vivo functional assays, including gene re-expression studies.
Main Results:
- Resistant AML cells exhibit proliferation independent of BCL-2 signaling, suggesting bypass mechanisms.
- Neuroactive ligand-receptor interaction (NLRI) pathway identified as a key signaling node in resistance.
- Downregulation of CHRNB4 in resistant cells correlates with aggressive phenotypes and poor clinical response.
Conclusions:
- The NLRI pathway plays a significant role in venetoclax resistance in AML.
- CHRNB4 is a potential prognostic biomarker and therapeutic target for AML treatment strategies.
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