A recent discovery may enhance treatment for drug-resistant leukemia.

In one out of six cancer cases, genetic alterations are present in humans; however, only a few studies have been able to determine how this affects treatment outcomes.

 

In 2020, leukemia (a type of blood cancer) accounted for approximately 2.5 percent of all new malignant tumor cases and 3.1 percent of deaths worldwide. One subtype of this disease is chronic myeloid leukemia (CML), which primarily affects the bone marrow that produces blood cells.

 

Duke-NUS scientists, in collaboration with their partners, developed the first preclinical model featuring a genetic variation common among the East Asian population, which includes Chinese, Japanese, and Koreans. About 12-15 percent of individuals from this region have a hereditary genetic variation in a protein called BCL-2, which interacts with the pro-apoptotic protein BIM, crucial for regulating the elimination of damaged or unwanted cells.

Researchers conducted a series of experiments demonstrating that the presence of variations leads to the production of alternative versions of the BIM protein, which, in turn, helps cancer cells evade destruction. As a result, tumor cells survive longer and can proliferate more aggressively, contributing to disease progression.

One of the most common treatments for chronic myeloid leukemia is a class of drugs known as tyrosine kinase inhibitors, with imatinib being the most widely used. However, patients with BIM variations often respond poorly to imatinib, resulting in fewer cancer cells being eradicated during treatment.

To better understand the mechanisms behind this process, the team utilized advanced gene profiling techniques to investigate how different tumor cells depend on various proteins for survival.

The lead author of the study, Dr. Yu Mengge, a researcher in the Duke-NUS Cancer and Stem Cell Biology Program, stated, “We found that leukemia cells with the BIM variation heavily rely on a protein called MCL-1 for survival. This significant discovery revealed a potential vulnerability in these imatinib-resistant malignant cells that can be targeted with new and more effective treatment strategies.”

Building on these insights, researchers tested a novel treatment approach that combined an MCL-1 blocker with imatinib: the results were promising, as the combination was much more effective at killing resistant leukemia cells than imatinib alone. This suggests that targeting MCL-1 could help address the resistance observed in chronic myeloid leukemia patients with the BIM variation and reduce the likelihood of disease progression.

For patients with such variations, this discovery could be groundbreaking.

Receiving the right oncology treatment as early as possible is crucial for improving outcomes and quality of life for patients. Given the prevalence of the BIM variation in the East Asian population, it is essential to understand its impact on cancer treatment. The results of this study suggest that conducting genetic testing for this variant at diagnosis could enhance treatment outcomes.

The findings may also have significant implications for other types of cancer, such as certain lung cancers, where the BIM protein is responsible for destroying tumor cells. Researchers hope to conduct further studies in this area to extend the benefits of precision medicine to a larger number of patients.