New Study Shows that Targeting Epigenetic Modifiers and Splicing Regulators Together May Offer New Treatment Strategies for AML

Treating acute myeloid leukemia (AML), a rapidly growing cancer of the blood and bone marrow in which immature white blood cells (myeloblasts) accumulate, crowd out healthy cells, leading to symptoms such as fatigue, easy bruising/bleeding, fever, and frequent infections, greatly depends on understanding what goes wrong inside cells.

A new study suggests that two genetic mutations – IDH2 and SRSF2 – act in concert to mis-splice RNA transcripts and alter blood cell development. The findings were published in the January 2, 2026, issue of Science Advances and provide a mechanistic map that could inform future therapies.[1]i

Isocitrate dehydrogenase (IDH) genes are common in AML, occurring in 20-30% of cases [2], while mutations in spliceosome genes (SRSF2 and others) correlate with poorer outcomes in patients treated with intensive chemotherapy for Acute Myeloid Leukemia.[3]

Genetic ‘scenes’
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. However, in AML, these two genetic mutations disrupt the editor’s script, creating a chaotic plot that drives the 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—interact to cause harm.

“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.

Mis-splicing of key transcriptional regulators
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 regulate gene expression and the splicing of RNA. Understanding both could help improve treatments.

“These mutations don’t act alone—they reshape the cell’s blueprint,” noted senior author, Maria Figueroa, M.D., associate director for Translational Research and professor of biochemistry and molecular biology at Sylvester.

“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,” Figueroa said.

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,” Telonis further noted.

Epigenetic modifiers and splicing regulators
The study suggests that targeting epigenetic modifiers and splicing regulators together may yield 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 explained.

“It’s early, but this mechanistic clarity gives us a foundation for combination approaches,” she concluded.

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.

Reference
[1] Telonis AG, Stanley RF, Adelman ER, Yoshimi A, Adele AA, Cruz A, Wiseman DH, Abdel-Wahab O, Figueroa ME. Synergistic intragenic epigenetic deregulation by IDH2 and SRSF2 mutations causes mis-splicing of key transcriptional regulators. Sci Adv. 2026 Jan 2;12(1):eadu8292. doi: 10.1126/sciadv.adu8292. Epub 2026 Jan 2. PMID: 41481703; PMCID: PMC12758512.
[2] Babakhanlou R, DiNardo C, Borthakur G. IDH2 mutations in acute myeloid leukemia. Leuk Lymphoma. 2023 Nov-Dec;64(11):1733-1741. doi: 10.1080/10428194.2023.2237153. Epub 2023 Jul 18. PMID: 37462435.
[3]  Berton G, Sedaki B, Collomb E, Benachour S, Loschi M, Mohty B, Saillard C, Hicheri Y, Rouzaud C, Maisano V, Villetard F, Corda ED’, Charbonnier A, Rey J, Hospital MA, Ittel A, Abbou N, Fanciullino R, Dadone-Montaudié B, Vey N, Venton G, Cluzeau T, Alary AS, Garciaz S. Poor prognosis of SRSF2 gene mutations in patients treated with VEN-AZA for newly diagnosed acute myeloid leukemia. Leuk Res. 2024 Jun;141:107500. doi: 10.1016/j.leukres.2024.107500. Epub 2024 Apr 15. PMID: 38636413.

Featured image: Maria Figueroa, M.D., associate director for Translational Research and professor of biochemistry and molecular biology at Sylvester Comprehensive Cancer Center (right) and Aristeidis Telonis, Ph.D., assistant professor of biochemistry and molecular biology at Sylvester Comprehensive Cancer Center (left). Photo courtesy:©: © 2025 – 2026 Sylvester Comprehensive Cancer Center. Used with permission.

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