ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1652373
This article is part of the Research TopicDiagnostic, Prognostic and Predictive Markers in LeukemiaView all 4 articles
The role of the lysine histone methylase KMT2D in chronic myeloid leukemia
Provisionally accepted
- 1Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany
- 2Universitatsklinikum Schleswig Holstein Institut fur Humangenetik, Kiel, Germany
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Chronic myeloid leukemia (CML) can be effectively treated inhibiting the disease-causing BCR::ABL1 kinase by tyrosine kinase inhibitors (TKIs). Although therapy is initially tremendously successful, resistance may occur in up to 25 % of CML patients. Besides aberrations in the BCR::ABL1 kinase domain, a variety of resistance mechanisms are currently discussed, among them epigenetic reprogramming. The histone-modifying enzyme lysine methyltransferase 2D (KMT2D/MLL2) belongs to the most frequently mutated genes in cancer and is also known for its association with hereditary Kabuki syndrome. However, its role in CML is widely unknown. In the present study, we analyzed the role of the KMT2D p.(Arg191Trp) variant in imatinibresistant CML, which was recurrently acquired in imatinib resistance in vitro. SiRNAmediated KMT2D knockdown, but also introduction of the p.(Arg191Trp) variant into treatment-naïve K-562 cells led to impaired imatinib susceptibility visible by increased cell numbers, proliferation rates and metabolic activities under imatinib exposure (p < 0.001). The effect of KMT2D p.(Arg191Trp) could be overcome by inhibiting histone demethylation with the demethylase inhibitor LSD1. In addition, rescue of KMT2D expression in imatinib-resistant cells reinstated the response to imatinib treatment. Furthermore, gene expression analysis revealed upregulation of CCNE2 in cells harboring KMT2D p.(Arg191Trp) potentially explaining increase in cell proliferation under imatinib exposure. Overall, our findings demonstrate that the loss of the tumor suppressor KMT2D promotes TKI resistance in CML. Thus, KMT2D status could serve as an additional biomarker for TKI resistance, while restoration of its expression might be a therapeutic option to overcome this resistance.
Keywords: Chronic myeloid leukemia, Drug Resistance, Imatinib, KMT2D, epigenetics, histone modification Additional information
Received: 23 Jun 2025; Accepted: 25 Aug 2025.
Copyright: © 2025 Schlemminger, Nagel, Vater, Cascorbi and Kaehler. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Meike Kaehler, Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany
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