A1 Refereed original research article in a scientific journal
Drivers of clinical resistance to venetoclax and hypomethylating agents in acute myeloid leukemia and strategies for improving efficacy
Authors: Vänttinen, Ida; Saad, Joseph; Ruokoranta, Tanja; Kytölä, Sari; Qin, Guangrong; Tercan, Bahar; Ettala, Pia; Partanen, Anu; Pyörälä, Marja; Rimpiläinen, Johanna; Siitonen, Timo; Manninen, Mikko; Valk, Peter J. M.; Huls, Gerwin; Thorsson, Vésteinn; Heckman, Caroline A.; Kontro, Mika; Kuusanmäki, Heikki
Publisher: Wiley
Publication year: 2026
Journal: HemaSphere
Article number: e70282
Volume: 10
Issue: 1
eISSN: 2572-9241
DOI: https://doi.org/10.1002/hem3.70282
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Open Access publication channel
Web address : https://doi.org/10.1002/hem3.70282
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/508638390
Self-archived copy's licence: CC BY NC ND
Self-archived copy's version: Publisher`s PDF
The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) in combination with hypomethylating agents (HMAs) has improved treatment outcomes for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy and is increasingly used in the relapsed/refractory setting. However, primary resistance remains a significant challenge, affecting 20%–35% of treatment-naïve and around 50% of previously treated AML patients. To investigate the mechanisms driving primary resistance to VEN–HMA therapy, we analyzed genetic, transcriptomic, BCL-2 family protein expression, and ex vivo drug sensitivity data from 101 AML patients and correlated these profiles with clinical outcomes to VEN–HMA. Our study found that blasts from refractory patients exhibit an elevated BCL-XL/BCL-2 protein expression ratio, an immature CD34+CD38− phenotype, and frequent TP53 mutations. Consistent with the high ratio of BCL-XL/BCL-2, resistant samples showed increased ex vivo sensitivity to the dual BCL-2/BCL-XL inhibitor navitoclax. In addition, SMAC mimetics were effective in refractory blasts, which correlated with high TNF gene expression in these cells. Ex vivo treatment with the combination of navitoclax and SMAC mimetics further enhanced the eradication of VEN–HMA refractory blasts, although toxicity was also observed in healthy CD34+ cells. In conclusion, our integrative analysis identifies molecular signatures associated with primary VEN–HMA resistance and highlights BCL-2/BCL-XL inhibition and SMAC mimetics as therapeutic strategies to target resistance.
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Funding information in the publication:
This study was supported by the Cancer Foundation Finland, the Finnish Medical Foundation, the Helsinki University Hospital Comprehensive Cancer Center, the University of Helsinki, the iCAN–Digital Precision Medicine Flagship, the Sigrid Juselius Foundation and the National Cancer Institute of the National Institutes of Health under award number R01CA270210. H.K. is supported by the Finnish Cultural Foundation, H.K. and I.V. are supported by the Orion Research Foundation, and H.K. and M.K. are supported by the Foundation for the Finnish Cancer Institute. Open access publishing facilitated by Helsingin yliopisto, as part of the Wiley - FinELib agreement.
