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Methylation of PLK-1 Potentially Drives Bendamustine Resistance in Leukemia Cells
1Department of Pediatrics, Nippon Medical School, Tokyo, Japan
2Department of Pediatrics, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
Background: Drug resistance remains a significant impediment in leukemia treatment. While Bendamustine hydrochloride (BH) stands out as a promising therapeutic agent for non-Hodgkin's lymphoma and mantle cell lymphoma, the mechanisms of resistance to BH are not yet fully understood. Our study focuses on elucidating the mechanisms behind bendamustine resistance in leukemia cells, with a specific emphasis on epigenetics.
Methods: Bendamustine-resistant cells were cultivated from human B cell lymphoblastic leukemia cell lines through systematic and sustained exposure to bendamustine, using the limiting dilution method. Gene expression was assessed via real-time polymerase chain reaction, while the expression of the multidrug resistance protein 1 (MDR1) was evaluated using flow cytometry.
Results: Bendamustine-resistant leukemia cells exhibited a decreased RNA expression level for Polo-like kinase-1 (PLK-1). Notably, after treatment with the demethylating agent 5-aza-2'-deoxycytidine, PLK-1 gene expression surged significantly, enhancing bendamustine's cytotoxicity in the resistant leukemia cells. However, MDR1 expression, as determined by flow cytometry, remained consistent between parental and bendamustine-resistant leukemia cells.
Conclusions: Our findings indicate that the methylation of the PLK-1 gene plays a pivotal role in modulating PLK-1 expression and is central to the development of bendamustine resistance in leukemia cells.
J Nippon Med Sch 2024; 91: 162-171
Keywords
bendamustine hydrochloride, leukemia, drug resistance, PLK-1, MDR1
Correspondence to
Takeshi Asano, Department of Pediatrics, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba 270-1694, Japan
july1364@nms.ac.jp
Received, August 20, 2023
Accepted, October 4, 2023