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Background/objectives <p>Development of novel therapies for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is hindered by limited biomarkers to identify appropriate target populations and poor translatability of preclinical drug candidates. In this study, we sought to validate Fragile histidine triad diadenosine triphosphate (FHIT) deficiency as a predictive biomarker for decapping scavenger enzyme (DCPS)-targeted therapy in AML and MDS, and to identify clinically accessible proxy biomarkers.</p> Methods <p>We analyzed primary AML samples treated with the DCPS small-molecule inhibitor RG3039 to identify additional biomarkers beyond FHIT that predict treatment response. We analyzed a large cohort of clinical and multi-omics AML and MDS datasets to define FHIT-low prevalence and stratify patient populations eligible for DCPS-targeted therapy. </p> Results <p>Low FHIT expression predicted effective therapeutic response to DCPS inhibition; however, hydroxyurea pretreatment confounded the predictive value of FHIT. FHIT-low expression occurred in 5–24% of AML patients, with highest prevalence in pediatric populations (24.4%). In MDS, FHIT promoter methylation was present in 35.8% of patients and remained stable during treatment with the hypomethylating agent azacitidine, supporting MDS as a potential therapeutic indication. IDH2 mutation status served as a proxy biomarker for FHIT expression and DCPS sensitivity in AML.</p> Conclusions <p>FHIT expression levels predict sensitivity to DCPS inhibition and a large proportion of adult and pediatric AML as well as MDS patients are eligible for DCPS-targeted therapy. IDH2 mutation status is a clinically accessible proxy biomarker for predicting FHIT expression levels and sensitivity to DCPS inhibition in AML.</p>

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Integrated FHIT and IDH2 biomarker profiling predicts lethal sensitivity to DCPS inhibition in Acute Myeloid Leukemia and Myelodysplastic syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Francesca Grassi,
  • Lisa Bast,
  • Madhurendra Singh,
  • Magnus Tobiasson,
  • Julian Walfridsson,
  • Angelo de Milito,
  • Martin Andersson,
  • Andreas Höglund

摘要

Background/objectives

Development of novel therapies for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is hindered by limited biomarkers to identify appropriate target populations and poor translatability of preclinical drug candidates. In this study, we sought to validate Fragile histidine triad diadenosine triphosphate (FHIT) deficiency as a predictive biomarker for decapping scavenger enzyme (DCPS)-targeted therapy in AML and MDS, and to identify clinically accessible proxy biomarkers.

Methods

We analyzed primary AML samples treated with the DCPS small-molecule inhibitor RG3039 to identify additional biomarkers beyond FHIT that predict treatment response. We analyzed a large cohort of clinical and multi-omics AML and MDS datasets to define FHIT-low prevalence and stratify patient populations eligible for DCPS-targeted therapy.

Results

Low FHIT expression predicted effective therapeutic response to DCPS inhibition; however, hydroxyurea pretreatment confounded the predictive value of FHIT. FHIT-low expression occurred in 5–24% of AML patients, with highest prevalence in pediatric populations (24.4%). In MDS, FHIT promoter methylation was present in 35.8% of patients and remained stable during treatment with the hypomethylating agent azacitidine, supporting MDS as a potential therapeutic indication. IDH2 mutation status served as a proxy biomarker for FHIT expression and DCPS sensitivity in AML.

Conclusions

FHIT expression levels predict sensitivity to DCPS inhibition and a large proportion of adult and pediatric AML as well as MDS patients are eligible for DCPS-targeted therapy. IDH2 mutation status is a clinically accessible proxy biomarker for predicting FHIT expression levels and sensitivity to DCPS inhibition in AML.