New Insights into Leukemia Resistance Mechanism May Transform Treatment Approaches

Recent research conducted by scientists at The Jackson Laboratory has unveiled a significant molecular mechanism that allows acute myeloid leukemia (AML) cells to resist chemotherapy. This breakthrough could pave the way for more effective treatment strategies for this aggressive form of blood cancer, which represents 80% of acute leukemia cases in adults.

The study, published in Blood Cancer Discovery, highlights the role of a protein known as RUNX1C, an isoform of the RUNX1 gene. Researchers discovered that changes in DNA methylation--a chemical modification to DNA--can activate RUNX1C, leading to a heightened resistance to chemotherapy in AML cells.

By analyzing patient data collected before and after chemotherapy treatment, the research team found that the RUNX1C protein increased in response to treatment failure. This protein triggers the expression of BTG2, a gene that slows down the cell cycle and induces a dormant state in leukemia cells, making them less susceptible to chemotherapy, which is most effective when cancer cells are actively dividing.

Currently, there are no effective treatments for patients who experience a relapse after chemotherapy, underscoring the importance of this research. Understanding the role of RNA isoforms like RUNX1C in chemoresistance is crucial for developing new therapeutic strategies.

In laboratory experiments, the team employed RNA-targeting tools to inhibit RUNX1C in AML models, both in cultured cells and animal models. The combination of RUNX1C inhibition with standard chemotherapy significantly enhanced the efficacy of the treatment, reviving dormant leukemia cells to an active state where chemotherapy could effectively target them.

Lead researcher Dr. Cuijuan Han indicated that the overexpression of RUNX1C leads to resistance against multiple chemotherapy agents used in AML treatment. Conversely, knocking out this isoform results in increased sensitivity to these drugs.

Looking forward, the laboratory is collaborating with other institutions to advance the application of antisense oligonucleotides (ASOs)--a promising technology that binds to RNA to prevent the production of specific proteins. If future studies validate these findings, targeting RUNX1C with ASOs could become a vital strategy in combating AML.

While the current research is focused on AML, the implications of targeting RNA isoforms may extend to other cancer types, suggesting a broader potential application for enhancing drug responses across various malignancies.