Dual Genetic Mutations Drive RNA Mis-Splicing and Leukemia Progression

Treating acute myeloid leukemia (AML) depends on knowing what goes wrong inside cells. A new study suggests that two genetic mutations – IDH2 and SRSF2 – work cooperatively to mis-splice RNA messages and change how blood cells develop. The findings appear in the Jan. 2 issue of Science Advances and 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 AML, these two genetic mutations throw the editor off script, creating a chaotic plot that drives disease.

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 Comprehensive Cancer Center at the University of Miami Miller School of Medicine discovered that the two mutations-IDH2 and SRSF2-team up to cause trouble.

"When those two forces collide, the editing room becomes chaos," said first author Aristeidis Telonis, Ph.D., assistant professor of biochemistry and molecular biology at Sylvester.

The study shows this synergy leads to mis-splicing of key transcriptional regulators-the master switches that determine cell identity.

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. 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."

Maria Figueroa, M.D., senior author, associate director for Translational Research and professor of biochemistry and molecular biology at Sylvester

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 Telonis. "This link opens the doors for future trials to explore the use of epigenetic therapies in AMLs with these two mutations."

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-suggesting a potential therapeutic angle.

"We're beginning to see how these vulnerabilities could be exploited," Figueroa added. "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, mis-splicing 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.