ISAL 2025 | Identifying potential targets for treating SRSF2-mutated AML

So SRSF2 is one of the most common splicing mutations that leads to AML. If you find an SRSF2 mutation in a healthy individual, there is a very high risk that they will progress towards AML, as this mutation has high penetrance as opposed to other clonal hematopoiesis mutations. AMLs with SRSF2 are high-risk AMLs, and currently there are no targeted therapies specifically targeting SRSF2 among AML patients or among healthy individuals. What we basically did, we inserted SRSF2 mutations into different cell lines and did a synthetic lethality drug screen to identify Achilles heels or weak spots in the AMLs who have now SRSF2 mutations. This drug screen demonstrated a unique molecule, a ROCK inhibitor, which specifically targeted AML cells carrying SRSF2 mutation. What we saw is that when we add ROCK inhibitors, so it’s a Rho kinase inhibitor, in two cells that carry SRSF2, we see dramatic changes in cell cycle. So SRSF2 mutated AMLs got stuck both in S phase and M phase once added the ROCK inhibitor. When we looked at these cells under electron microscopy, it was clear that the nuclear envelope, so the lamin of the SRSF2-muted cells became highly distorted and with huge regions that created that prevented the cell from replicating. We did not understand why SRSF2 mutation do that, but more analysis from single-cell RNA-seq and RNA-seq data suggested that SRSF2 plays a role in cell cycle, specifically in S and M phase, which was not known before. So, it is supposedly a splicing factor which coordinates the splicing of unspliced RNA. For reasons we do not understand, we believe now that SRSF2 also plays a role in cell cycle. And SRSF2 mutated cells have a distorted cell cycle, and once you add the ROCK inhibitor, the cell cycle is even much more distorted, so the cells cannot complete the cell cycle and therefore die. So this is now our hypothesis, how one can use specific cell cycle inhibitors to target SRSF2 mutated AML. Yes, it is indeed an unmet need and there are no targeted therapies. And I even think another important use of it will be in identifying healthy individuals who carry SRSF2, which we know that will develop AML, and we can try to offer them an early intervention or even preventive therapies. Other possible drugs are being tested but none currently is in Phase II clinical trials. It’s still an unmet need and I hope we and others will continue to provide more targeted and more efficacious drug. We are now moving to do such drug screens on human AMLs, primary human AMLs and not cell lines and try to better improve our SRS2 targeting drugs.

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