One protein may hold the key to fixing leukemia treatment failure

The team pinpointed a protein that enables cancer cells to alter the shape of their mitochondria, the structures that generate cellular energy. This remodeling shields the cells from venetoclax (brand name, Venclexta), a common therapy for acute myeloid leukemia that often becomes less effective over time.

When scientists blocked this protein in mice carrying human acute myeloid leukemia, the experimental compounds restored venetoclax activity and extended the animals' survival.

The study, published in Science Advances, highlights an unexpected form of drug resistance and offers a potential new direction for treating one of the most lethal blood cancers in adults.

How Altered Mitochondria Help Leukemia Cells Survive

"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's Pediatric Hematology and Oncology Research Center of Excellence (NJPHORCE).

Venetoclax can push many acute myeloid leukemia patients into remission by triggering cancer cell death. However, nearly all patients eventually develop resistance. The five-year survival rate remains 30 percent, and the disease claims about 11,000 lives in the United States each year.

OPA1 Identified as a Key Driver of Resistance

Through electron microscopy and genetic screens, Glytsou's team determined that treatment-resistant leukemia cells produce unusually high amounts of OPA1, a protein that organizes the inner structure of mitochondria. Cells with elevated OPA1 develop tightly packed, more numerous folds in their mitochondrial membranes, known as cristae, which trap cytochrome c. Under normal conditions, cytochrome c escapes from the mitochondria to initiate cell death.

Researchers verified these findings in samples from leukemia patients. Individuals who had relapsed after therapy had significantly narrower cristae than newly diagnosed patients, with the most dramatic differences appearing in those previously treated with venetoclax.

Blocking OPA1 Restores Drug Sensitivity

To determine whether inhibiting this structural reshaping could restore treatment response, the team tested two experimental OPA1 inhibitors. In mice transplanted with human leukemia cells, adding the OPA1 inhibitors to venetoclax at least doubled survival time compared with venetoclax alone.

The combined approach was effective across multiple leukemia subtypes, including those with p53 mutations that are typically linked to poor outcomes and strong drug resistance.

Additional Weaknesses Revealed in Resistant Cells

The results also suggest that OPA1 inhibitors may have benefits beyond restoring standard cell death pathways. Experiments showed that cells lacking OPA1 rely heavily on the nutrient glutamine and become susceptible to ferroptosis, an iron-driven form of cell death that results from lipid damage.

Importantly, mouse studies indicated that these compounds did not interfere with normal blood cell development, which is essential when considering new leukemia treatments for people.

Early-Stage Work With Broad Potential

The research remains in its early stages. The OPA1 inhibitors, created by collaborators at the University of Padua in Italy, are still lead compounds and will require further refinement before clinical testing can begin.

"There is still some time to go through," Glytsou said, noting that a third generation of compounds may be needed to improve solubility and other drug properties.

Even so, Glytsou believes this work points toward a promising therapeutic direction for stubborn leukemia cases and possibly other cancers as well. She is also a member of the cancer institute's cancer pharmacology and cancer metabolism and immunology research programs.

OPA1 is overexpressed in several cancer types and is linked with poor outcomes and therapy resistance in breast cancer, lung cancer and other malignancies.

Rutgers Cancer Institute, in partnership with RWJBarnabas Health, is New Jersey's only National Cancer Institute-designated Comprehensive Cancer Center.