Researchers have discovered that an isoform of the transcription factor RUNX1 orchestrates chemoresistance in patients with acute myeloid leukemia (AML), according to findings published in Blood Cancer Discovery. They identified that the long-isoform RUNX1C's connection to BTG2 may enable cellular quiescence of the leukemia cells so they can evade chemotherapy.
Based on these findings, the study authors, led by Cuijuan Han, PhD, Associate Research Scientist at The Jackson Laboratory, explored RNA-based targeting of RUNX1C as a way to reactivate the leukemia cells and improve their response to chemotherapy.
Key Study Findings
The researchers conducted an analysis of the RNA-isoform landscape in patients with AML and analyzed changes in RNA isoforms from before chemotherapy to at relapse to explore molecular mechanisms of chemoresistance.
“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,” explained team leader Eric Wang, PhD, Assistant Professor at The Jackson Laboratory. “Scientists have done extensive RNA-isoform analysis but not in the context of acute myeloid leukemia relapse. Our study is a good resource to show that in addition to genes, RNA isoforms are also very important in mediating chemoresistance.”
Intragenic DNA methylation was identified at the proximal promoter of the RUNX1 gene, which led to greater expression of the RUNX1C isoform. The isoform had a unique N-terminal region allowing for regulation of direct target genes, including BTG2. BTG2 impacts the cells’ RNA by removing the ribosomal RNA poly(A) tails, a process called deadenylation, which leads to decreased protein synthesis and cellular stability or quiescence. In the quiescent state, the leukemia cells were able to better resist chemotherapy.
“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,” Dr. Han said.
The researchers found that if they deleted the ribosomal RNAs, cellular quiescence increased. But, if they targeted RUNX1C, it reactivated the quiescent cells and reenabled the cells’ sensitivity to chemotherapy.
In cultured cells and mouse models, the study authors explored the use of RUNX1C inhibition in combination with standard chemotherapy for AML. Antisense oligonucletodies were used to target and bind to the RNA of RUNX1 and prevent it from making isoforms like RUNX1C. The combination led to a disruption in the quiescent state and a return of the activity of the leukemia cells, which could be killed by the chemotherapy.
This antisense oligonucleotide technology has yet to be widely used in cancer research and is still in the experimental stages of study in rare neurologic diseases. The study authors, however, believe that if further studies confirm their results, then antisense oligonucleotide targeting of RUNX1C could become a powerful tool in the fight against AML.
“Our study provides a proof of principle that knocking down isoforms with the right technology could enhance or even overcome chemoresistance,” Dr. 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.”
Disclosure: For full disclosures of the study authors, visit aacrjournals.org.
