Acute myeloid leukemia (AML) is the most common acute hematologic malignancy in adults and one of those with the poorest prognosis. Unlike other hematologic diseases, therapeutic advances in AML have historically been modest, and overall survival remains limited, largely due to the persistence of treatment-resistant cellular subpopulations. Understanding the biological mechanisms that explain why some patients respond better than others to the same therapy is one of the main current challenges in this field.
Recently, the introduction of targeted therapies has represented a relevant advance in the treatment of AML. Among them, venetoclax, an inhibitor of the BCL-2 protein, has been shown to improve clinical outcomes both in newly diagnosed patients and in those with refractory or relapsed disease. However, responses to this treatment are highly variable, and a significant proportion of patients exhibit primary resistance or develop secondary resistance, which limits its long-term efficacy.
In this context, a study led by Dr. Manel Esteller, head of the Cancer Epigenetics group at the Institut de Recerca Sant Pau (IR Sant Pau), analyzed whether epigenetic mechanisms could help explain this heterogeneity in therapeutic response. “We were interested in understanding why some tumors respond better than others to treatments such as venetoclax and whether epigenetics could help explain it,” notes Dr. Esteller. The work has been published in the journal British Journal of Haematology.
Epigenetics studies changes that regulate gene activity without modifying the DNA sequence and allows the same genetic information to be expressed differently depending on the cellular context. Among the main epigenetic mechanisms is DNA methylation, a chemical mark that can silence gene expression and whose alteration has been associated both with cancer development and with responses to different oncologic treatments.
Based on this conceptual framework, the research team designed a large-scale study focused on integrating different layers of molecular information. To this end, they carried out an extensive computational biology analysis combining DNA methylation data, gene expression profiles, and drug response data in a collection of nearly 180 cell lines derived from leukemias, lymphomas, and other hematologic malignancies. This is an experimental model widely used for this type of systematic approach.
Approximately 850,000 DNA regions associated with epigenetic regulation were analyzed in this study, making it possible to generate a highly detailed map of genome-wide methylation patterns. These data were integrated with information on the expression levels of thousands of genes and with quantitative measures of drug response. “We wanted to go beyond analyzing a single gene or a single pathway, and that is why we integrated different levels of molecular information. This approach allowed us to identify epigenetic patterns associated with treatment response,” explains Dr. Esteller.
The integrated data analysis identified a small set of genes whose epigenetic regulation showed a particularly consistent association with sensitivity to venetoclax. Among them, EIF5A2 stood out, as hypermethylation in its regulatory regions was reproducibly associated with reduced gene expression and with greater treatment efficacy.
EIF5A2 encodes a factor involved in the regulation of protein synthesis and in cellular processes that are fundamental for cell survival and proliferation. Although its involvement in different tumor contexts had been described previously, its potential role in responses to targeted therapies in AML had not been explored until now, giving this finding additional biological interest.
“The integrated analysis allowed us to prioritize genes with a solid association with treatment response, and EIF5A2 stood out not only because of its epigenetic profile, but also because it offered a clear functional hypothesis that could be tested in the laboratory,” explains Dr. Esteller. This reasoning was key to moving from computational identification of the candidate to its experimental evaluation.
The experiments consistently confirmed that EIF5A2 activity influences the response to venetoclax in cellular models of AML. Cell lines with hypermethylation of regulatory regions of this gene showed reduced RNA and protein levels and exhibited significantly greater sensitivity to treatment, whereas those in which EIF5A2 remained active tended to be more resistant.
“The bioinformatic prediction only made sense if it was experimentally confirmed, and it was crucial to show that loss of EIF5A2 activity was consistently associated with increased sensitivity to the drug,” explains Dr. Esteller. In addition, reactivation of gene expression using demethylating agents partially reversed this effect, reinforcing the direct relationship between epigenetic regulation, gene expression, and treatment response.
Taken together, these results establish a functional link between epigenetic regulation of EIF5A2 and venetoclax efficacy in experimental AML models, consolidating the biological validity of the findings obtained through computational analysis.
EIF5A2 encodes a protein that requires a highly specific chemical modification, known as hypusination, to be functional. This process depends on specific enzymes and on the availability of certain cellular polyamines, making this pathway a potentially relevant regulatory checkpoint from a biological standpoint.
Building on this knowledge, the researchers explored whether pharmacological inhibition of EIF5A2 activation could modify the response to venetoclax. In experimental models, combining venetoclax with a preclinical inhibitor of this process increased the sensitivity of initially resistant cells, while it did not produce an additional effect in cells that were already responsive to treatment.
These results suggest that EIF5A2 activity may play a relevant role in mechanisms of resistance to venetoclax and provide an initial functional insight into how this pathway could influence treatment efficacy.
Although the study was conducted in experimental models and through retrospective analysis of available data, the authors emphasize that the results should be interpreted with caution. “This work does not change current clinical practice, but it provides a solid biological basis for further research on how to optimize the use of venetoclax and how to address treatment resistance in AML,” adds Dr. Esteller.
Overall, the study reinforces the value of epigenetic research in understanding variability in responses to oncologic treatments and lays the groundwork for future studies to evaluate these hypotheses in the context of controlled clinical trials. The goal is to advance toward increasingly personalized therapeutic approaches in hematologic diseases.
Crespo-García E, Quero-Dotor C, Noguera-Castells A, Sancho-Vila L, Martinez-Verbo L, Esteller M. Epigenetic silencing and pharmacological inhibition of EIF5A2 foster venetoclax sensitivity in acute myeloid leukaemia. Br J Haematol 2026. https://doi.org/10.1111/bjh.70339
