Routine Genetic Marker May Help Guide Targeted Therapy in Acute Leukemia

Acute myeloid leukemia (AML) is an aggressive blood cancer with widely variable treatment outcomes between patients. Choosing which individuals will benefit from targeted agents remains difficult, limiting precision in routine care. Many genomic alterations are already tested at diagnosis, but few reliably indicate therapeutic response. A new study shows that a routinely assessed mutation may help identify patients who respond to a drug that inhibits the enzyme DCPS.

Karolinska Institutet (Stockholm, Sweden) researchers identified low levels of the protein fragile histidine triad (FHIT) as a marker of sensitivity to DCPS inhibition. The authors report that AML patient samples with reduced FHIT are responsive to DCPS‑targeted treatment. They also point to an existing genetic assay—IDH2 mutation testing—that can capture this biology.

The key observation is that patients with an IDH2 mutation often have low FHIT levels and respond better to DCPS‑targeted therapy. Because IDH2 is already part of routine diagnostic testing at AML diagnosis, the marker can be used without adding new assays. This approach may streamline trial design by narrowing enrollment to patients most likely to benefit.

The team tested 24 primary AML samples with RG3039, a compound that blocks DCPS activity, and analyzed publicly available patient datasets to examine links between FHIT expression and genetic alterations. Across AML cohorts, the proportion with low FHIT ranged from 5% to 24%, with the highest proportion observed in children. 

In the related blood disorder myelodysplastic syndrome (MDS), approximately 36% of patients showed silencing of the FHIT gene. Together, these data suggest a defined subgroup in which DCPS inhibition warrants focused evaluation.

The findings were published in Discover Oncology. The researchers plan to validate the results in larger patient cohorts and to further investigate the biological connection between IDH2 mutations and FHIT expression. In the longer term, they hope these data will inform the design of a clinical study of DCPS‑targeted therapy in AML.

“Many promising cancer drugs fail in clinical trials because they are tested in very broad patient groups,” said Francesca Grassi, doctoral student at the Department of Medicine, Huddinge, Karolinska Institutet, and first author of the study. "By using a biomarker that is already available in health care, patient selection can be made both simpler and more precise."

“The IDH2 mutation captures the information we need to identify the right patients, without additional analyses. This could facilitate the planning of future clinical trials, particularly for patient groups with limited treatment options,” said Grassi.

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