RNA Splicing Errors Drive Leukemia
Summary
- A new study from Sylvester Comprehensive Cancer Center reveals how two mutations cooperate to erroneously splice RNA messages and disrupt the cell’s identity.
- The genes IDH2 and SRSF2 affect two key systems: the chemical signals that control gene expression and the way RNA is spliced. Understanding both could help improve treatments for AML.
- The findings, published in Science Advances, provide a mechanistic map that could inform future therapies.
Picture a film editor piecing together a blockbuster. Each scene must flow seamlessly to tell the story. In our cells, RNA plays that script editing role, splicing together genetic “scenes” so proteins know their lines.
But in acute myeloid leukemia (AML), two genetic mutations, IDH2 and SRSF2, throw the editor off script, creating a chaotic plot that drives disease.
A new study from Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, reveals how these mutations cooperate to erroneously splice RNA messages and disrupt the cell’s identity. The findings, published in Science Advances, provide a mechanistic map that could inform future therapies. The study was written by first author Aristeidis Telonis, Ph.D., with senior author Maria “Ken” Figueroa, M.D.
What’s Happening Inside the Cell
In healthy cells, splicing trims and joins RNA segments to produce accurate instructions for making proteins. Think of it as cutting and pasting dialogue to make the movie make sense. The SRSF2 gene acts like a casting director, choosing which lines stay. IDH2, meanwhile, influences the chemical “stage,” the epigenetic marks that guide those choices. Scientists at Sylvester discovered that the two mutations team up to cause trouble.
“When those two forces collide, the editing room becomes chaos,” said Dr. Telonis, assistant professor of biochemistry and molecular biology at the Miller School.
The study shows this synergy leads to mis-splicing of key transcriptional regulators—the master switches that determine cell identity.
Why It Matters
Treating AML depends on knowing what goes wrong inside cells. IDH2 and SRSF2 affect two key systems: the chemical signals that control gene expression and the way RNA is spliced. Understanding both could help improve treatments.
“These mutations don’t act alone. They reshape the cell’s blueprint,” said Dr. Figueroa. “When structure and chemical signals work together in the wrong way, the cell’s identity changes. Understanding that process gives us a roadmap for better, more precise treatments.”
The urgency for understanding is there. AML is a fast-growing cancer that starts in the bone marrow, where blood cells are made. In 2025, more than 22,000 people were diagnosed with AML. It mostly affects older adults, but it can occur in younger people as well.
AML happens when immature white blood cells grow out of control and crowd out healthy cells. Standard treatments include chemotherapy, targeted drugs and sometimes stem cell transplants. While these treatments can help, AML is hard to cure because the cancer cells often change and resist therapy. Each patient’s disease can look different at the genetic level, which makes finding the right treatment challenging.
The Science Behind the Scenes
The team studied patient samples and lab models using advanced tools to read RNA and map chemical changes in DNA. Here’s what they found:
• When both mutations are present, cells make more splicing errors than when only one mutation is present.
• These mistakes often occur near sites where DNA’s chemical tags have changed, suggesting a link between splicing errors and epigenetic changes.
• The genes most affected are long and complex, which makes them easier to disrupt.
Researchers used artificial intelligence to predict splicing mistakes based on DNA’s chemical patterns.
“Our model shows that methylation patterns alone can predict splicing outcomes,” said Dr. Telonis. “This link opens the doors for future trials to explore the use of epigenetic therapies in AMLs with these two mutations.”
Implications for Future Cancer Therapies
The study hints that targeting epigenetic modifiers and splicing regulators together might offer new treatment strategies. In lab tests, cells carrying both mutations showed heightened sensitivity to romidepsin, a drug that inhibits chromatin-modifying enzymes. That finding suggests a potential therapeutic angle.
“We’re beginning to see how these vulnerabilities could be exploited,” said Dr. Figueroa, Sylvester’s associate director of translational research and a professor of biochemistry and molecular biology at the Miller School. “It’s early, but this mechanistic clarity gives us a foundation for combination approaches.”
Cells rely on precise RNA editing to stay on script. In AML with IDH2 and SRSF2 mutations, the epigenetic notes and the editing machine reinforce each other’s mistakes, disrupting the very regulators that keep identity intact. Mapping that error pathway is a critical step toward therapies that restore the right messages or silence the wrong ones.
Tags: Acute Myeloid Leukemia, AI, AML, artificial intelligence, biochemistry and molecular biology, cancer research, chemotherapy, Dr. Aristeidis Telonis, Dr. Maria Figueroa, gene editing, Leukemia, Sylvester Comprehensive Cancer Center, technology