understanding Chemoresistance in AML

One of the biggest challenges in cancer treatment is that certain cancers reappear after chemotherapy-adn 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 possibly disarm it.

The Role of RUNX1C

In findings newly published in Blood Cancer Finding, 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.

How RUNX1C Promotes Dormancy

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 were 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.

implications for Future Treatment

“The problem right now is that there is no treatment for patients who relapse, and that’s why our study is so crucial-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 critically important in mediating chemoresistance.”

If a safe and targeted way can be developed to block RUNX1C, it could prevent cancer cells from slipping into quiescence, making chemotherapy more effective and reducing the risk of relapse, Wang said. The team tested RNA-targeting tools against RUNX1C in both cultured cells and in mice.

Pairing RUNX1C inhibition with chemotherapy significantly improved the drugs’ ability to kill leukemia cells.