One of the biggest challenges in cancer treatment is that certain cancers reappear after chemotherapy—and an aggressive type of blood cancer called acute myeloid leukemia (AML) is notorious for this. Now, new research from The Jackson Laboratory (JAX) points to a previously unknown molecular mechanism behind that chemoresistance, and a way to potentially disarm it.
In findings newly published in Blood Cancer Discovery , a team led by JAX assistant professor Eric Wang reports on the role of a protein called RUNX1C in this mechanism. A little-known variation, or “isoform” of a gene called RUNX1, the RUNX1C protein helps regulate how blood cells resist chemotherapy.
By studying data from AML patients from before they received chemotherapy and again after their cancer returned, the team found that in many cases a chemical tag known as DNA methylation had appeared in a section of the genome that normally controls the RUNX1 gene. That small change flipped a genetic switch, forcing cancer cells to make more of the RUNX1C isoform, activating a mechanism that made them far better at withstanding chemotherapy.
Specifically, RUNX1C turned on a gene called BTG2. This interfered with the cells’ RNA, slowing down cell activity and pushing leukemia cells into a dormant or quiescent state where they stop dividing. In this state, cancer cells effectively hide from chemotherapy, which works best when cancer cells are actively dividing. In other words, dormant cancer cells go unnoticed and can “wake up” after treatment.
“The problem right now is that there is no treatment for patients who relapse, and that’s why our study is so important—not just to understand what isoforms or genes mediate resistance but to understand how we can target them in the future,” Wang said. “Scientists have done extensive RNA isoform analysis but not in the context of AML relapse. Our study is a good resource to show that in addition to genes, RNA isoforms are also very important in mediating chemoresistance.”
If a safe and targeted way can be developed to block RUNX1C in patients, it could prevent cancer cells from slipping into quiescence, making chemotherapy more effective and reducing the risk of relapse, Wang said. The team tested two RNA-targeting tools against RUNX1C in AML models both in cultured cells and in mice.
Pairing RUNX1C inhibition with standard chemotherapy significantly improved the drugs’ ability to kill leukemia cells. Without the isoform’s influence, the dormant cancer cells “woke up” and started dividing again—precisely the state when chemotherapy is most effective.
Dr. Cuijuan Han, the lead author of the study, explained, “We demonstrated that overexpressing this isoform confers resistance to many of the chemotherapy treatments used for AML. We’ve done experiments to do the inverse, where we also knocked out the isoform and see that it confers sensitivity.”
Wang’s lab is collaborating with other organizations to continue using these RNA-targeting tools, known as antisense oligonucleotides (ASOs), which can bind to RNA and block it from making certain proteins like RNA isoforms. If further studies confirm the results, targeting RUNX1C with ASO technology could become a powerful tool in the fight against AML, Wang said. While this technology is in experimental stages for rare neurological diseases at JAX, it hasn’t been widely applied to AML or most other cancers.
“Our study provides a proof of principle that knocking down isoforms with the right technology could enhance or even overcome chemoresistance,” Wang said. “Although our lab does not focus on other cancers, applying this concept to other cancers may provide rationale to focus on whether targeting RNA isoforms can modulate drug response with different drugs and different cancers.”
Eric Wang was supported by The Jackson Laboratory Cancer Center (JAXCC) New Investigator Award (P30CA034196), JAX start-up funds, JAX Cancer Center Fast Forward Award, Leukemia Research Foundation (LRF), and Butler Family Foundation.