Scientists at The Jackson Laboratory are learning new therapeutic targets for acute myeloid leukemia (AML), an aggressive hematological malignancy that accounts for 80% of acute leukemia instances in adults. Credit score: The Jackson Laboratory
One of many greatest challenges in most cancers therapy is that sure cancers reappear after chemotherapy—and an aggressive kind of blood most cancers known as acute myeloid leukemia (AML) is infamous for this. Now, new analysis from The Jackson Laboratory (JAX) factors to a beforehand unknown molecular mechanism behind that chemoresistance, and a solution to doubtlessly disarm it.
In findings newly printed in Blood Most cancers Discovery, a group led by JAX assistant professor Eric Wang reviews on the function of a protein known as RUNX1C on this mechanism. A bit-known variation, or “isoform” of a gene known as RUNX1, the RUNX1C protein helps regulate how blood cells resist chemotherapy.
By learning knowledge from AML sufferers from earlier than they obtained chemotherapy and once more after their most cancers returned, the group discovered that in lots of instances a chemical tag often called DNA methylation had appeared in a piece of the genome that usually controls the RUNX1 gene. That small change flipped a genetic change, forcing most cancers cells to make extra of the RUNX1C isoform, activating a mechanism that made them much better at withstanding chemotherapy.
Particularly, RUNX1C turned on a gene known as BTG2. This interfered with the cells’ RNA, slowing down cell exercise and pushing leukemia cells right into a dormant or quiescent state the place they cease dividing. On this state, most cancers cells successfully cover from chemotherapy, which works finest when most cancers cells are actively dividing. In different phrases, dormant most cancers cells go unnoticed and may “wake up” after therapy.
“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 stated. “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.”
JAX assistant professor Eric Wang research mechanisms of drug resistance in hematological malignancies with the primary aim to develop new therapeutic methods and offering a blueprint for clinically related biomarkers. Credit score: The Jackson Laboratory
If a secure and focused means will be developed to dam RUNX1C in sufferers, it might stop most cancers cells from slipping into quiescence, making chemotherapy more practical and lowering the chance of relapse, Wang stated. The group examined two RNA-targeting instruments towards RUNX1C in AML fashions each in cultured cells and in mice.
Pairing RUNX1C inhibition with customary chemotherapy considerably improved the medicine’ potential to kill leukemia cells. With out the isoform’s affect, the dormant most cancers cells “woke up” and began dividing once more—exactly the state when chemotherapy is best.
Dr. Cuijuan Han, the lead writer of the examine, defined, “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 different organizations to proceed utilizing these RNA-targeting instruments, often called antisense oligonucleotides (ASOs), which may bind to RNA and block it from making sure proteins like RNA isoforms. If additional research affirm the outcomes, focusing on RUNX1C with ASO expertise might turn out to be a robust software within the battle towards AML, Wang stated. Whereas this expertise is in experimental levels for uncommon neurological illnesses at JAX, it hasn’t been extensively utilized to AML or most different cancers.
“Our study provides a proof of principle that knocking down isoforms with the right technology could enhance or even overcome chemoresistance,” Wang stated. “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.”
Extra info:
Cuijuan Han et al, An Isoform-Particular RUNX1C–BTG2 Axis Governs AML Quiescence and Chemoresistance, Blood Most cancers Discovery (2025). DOI: 10.1158/2643-3230.BCD-24-0327
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