Rutgers Scientists Identify Mitochondrial Mechanism Behind Venetoclax Resistance in Acute Myeloid Leukemia
核心洞察
Researchers from Rutgers Health (搜索) discovered that leukemia cells evade venetoclax treatment by producing high levels of OPA1 (搜索) protein, which reshapes mitochondria to prevent cell death.
The team found that treatment-resistant leukemia cells develop tighter mitochondrial cristae that trap cytochrome c, blocking the apoptosis pathway normally triggered by venetoclax.
Experimental OPA1 (搜索) inhibitors combined with venetoclax at least doubled survival time in mice with human leukemia cells compared to venetoclax alone.
Researchers from Rutgers Health (搜索) and collaborating institutions have identified a novel mechanism explaining why venetoclax, a standard treatment for acute myeloid leukemia, eventually fails in most patients. The team discovered that cancer cells evade treatment by producing elevated levels of a protein called OPA1 (搜索), which allows them to reshape their mitochondria in ways that protect against drug-induced cell death.
The findings, published in Science Advances, reveal an unexpected pathway of drug resistance and suggest a potential therapeutic approach for one of the deadliest blood cancers affecting adults.
Mitochondrial Remodeling Blocks Cell Death
"We found that mitochondria change their shape to prevent apoptosis, a type of cell suicide induced by these drugs," said senior study author Christina Glytsou, an assistant professor at Rutgers' Ernest Mario School of Pharmacy and Robert Wood Johnson Medical School and a member of the Rutgers Cancer Institute (搜索)'s Pediatric Hematology and Oncology Research Center of Excellence.
Using electron microscopy and genetic screens, Glytsou's team discovered that treatment-resistant leukemia cells produce high levels of OPA1 (搜索), a protein that controls the internal structure of mitochondria. Cells with elevated OPA1 levels develop tighter, more numerous folds in their mitochondrial membranes—compartments called cristae—that trap cytochrome c, a molecule that normally triggers cell death when released.
The researchers validated their findings by examining cells from leukemia patients. Those who had relapsed after treatment showed sharply narrower cristae than newly diagnosed patients, with the most pronounced changes observed in patients who had been treated with venetoclax.
Combination Therapy Shows Promise in Preclinical Models
To test whether blocking this structural change could restore drug efficacy, the team employed two experimental OPA1 (搜索) inhibitors developed by collaborators at the University of Padua in Italy. In mice transplanted with human leukemia cells, combining the OPA1 inhibitors with venetoclax at least doubled survival time compared with venetoclax alone.
The combination therapy demonstrated effectiveness across diverse leukemia subtypes, including cells with mutations in the p53 gene, which are strongly associated with treatment resistance and poor outcomes.
Multiple Mechanisms of Action
The OPA1 (搜索) inhibitors appear to work through additional mechanisms beyond restoring cell death pathways. The experiments revealed that cells lacking OPA1 become heavily dependent on the nutrient glutamine and vulnerable to ferroptosis, a different form of cell death driven by iron and lipid damage.
Importantly, tests in mice showed the compounds didn't harm normal blood cell production, a critical safety consideration for any potential leukemia treatment in humans.
Clinical Context and Future Directions
Although venetoclax induces remission in many acute myeloid leukemia patients by triggering cancer cell death, resistance develops in nearly all cases. The five-year survival rate remains at 30% and the disease kills about 11,000 Americans each year.
The research remains in early stages, with the OPA1 (搜索) inhibitors requiring further refinement before human testing can begin. "There is still some time to go through," Glytsou said, adding that a third generation of compounds may be needed to improve the drugs' solubility and other properties.
The work offers a promising direction for treating resistant leukemia and potentially other cancers. OPA1 (搜索) is overexpressed in multiple cancer types and associated with poor prognosis and therapy resistance in breast cancer, lung cancer and other malignancies, suggesting broader therapeutic applications for this approach.