Establishment and Characteristics of a Novel Mantle Cell Lymphoma-derived Cell Line and a Bendamustine-resistant Subline

Takimoto-Shimomura, Tomoko; Nagoshi, Hisao; Maegawa, Saori; Fujibayashi, Yuto; Tsukamoto, Taku; Matsumura-Kimoto, Yayoi; Mizuno, Yoshimi; Chinen, Yoshiaki; Mizutani, Shinsuke; Shimura, Yuji; Horiike, Shigeo; Kobayashi, Tsutomu; Kuroda, Junya

doi:10.21873/cgp.20080

Cited by 7 publications

(5 citation statements)

References 30 publications

(25 reference statements)

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“…Takimoto et al illustrated that the upregulation of ABCB1 and GST, prevalent in drug resistance pathways, aided the onset of resistance to BH. Additionally, they proposed that developing resistance to BH might concurrently escalate the risk of cross-resistance to other anti-lymphoma chemotherapeutics, such as DOX, melphalan, and VCR 12 . ABC transporters, membrane-spanning transporters, facilitate the transit of diverse substrates across cell membranes.…”

Section: Discussionmentioning

confidence: 99%

Methylation of PLK-1 Potentially Drives Bendamustine Resistance in Leukemia Cells

Itabashi,

Ueda,

Fukunaga

et al. 2024

J Nippon Med Sch

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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.

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Section: Discussionmentioning

confidence: 99%

Methylation of PLK-1 Potentially Drives Bendamustine Resistance in Leukemia Cells

Itabashi,

Ueda,

Fukunaga

et al. 2024

J Nippon Med Sch

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“…Second, the AKR1C3 single nucleotide polymorphism may influence the survival outcomes of patients receiving the CHOP regimen [ 69 ]. Finally, the role of ABC transporters in cancer responses to ANT-containing chemotherapy has been suggested in DLBCL [ 70 ], MCL [ 71 ], and Burkitt lymphoma [ 72 ]. In addition to the primary indication of BTK inhibitors in CLL and lymphomas, their efficacy has recently been demonstrated in AML and solid tumours [ 73 , 74 , 75 , 76 ].…”

Section: Discussionmentioning

confidence: 99%

Bruton’s Tyrosine Kinase Inhibitor Zanubrutinib Effectively Modulates Cancer Resistance by Inhibiting Anthracycline Metabolism and Efflux

et al. 2022

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Zanubrutinib (ZAN) is a Bruton’s tyrosine kinase inhibitor recently approved for the treatment of some non-Hodgkin lymphomas. In clinical trials, ZAN is often combined with standard anthracycline (ANT) chemotherapy. Although ANTs are generally effective, drug resistance is a crucial obstacle that leads to treatment discontinuation. This study showed that ZAN counteracts ANT resistance by targeting aldo-keto reductase 1C3 (AKR1C3) and ATP-binding cassette (ABC) transporters. AKR1C3 catalyses the transformation of ANTs to less potent hydroxy-metabolites, whereas transporters decrease the ANT-effective concentrations by pumping them out of the cancer cells. In our experiments, ZAN inhibited the AKR1C3-mediated inactivation of daunorubicin (DAUN) at both the recombinant and cellular levels. In the drug combination experiments, ZAN synergistically sensitised AKR1C3-expressing HCT116 and A549 cells to DAUN treatment. Gene induction studies further confirmed that ZAN did not increase the intracellular level of AKR1C3 mRNA; thus, the drug combination effect is not abolished by enzyme induction. Finally, in accumulation assays, ZAN was found to interfere with the DAUN efflux mediated by the ABCB1, ABCG2, and ABCC1 transporters, which might further contribute to the reversal of ANT resistance. In summary, our data provide the rationale for ZAN inclusion in ANT-based therapy and suggest its potential for the treatment of tumours expressing AKR1C3 and/or the above-mentioned ABC transporters.

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“…This study used four human MCL cell lines, Jeko‐1, JVM2, and Z138 obtained from American Type Culture Collection (ATCC) and KPUM‐YY1 established from a patient with MCL in our laboratory, 21 and the human embryonic kidney cell‐derived cell line HEK293T from ATCC. MCL cells were maintained in RPMI‐1640 (Wako) containing 10% fetal calf serum (Life Technologies), 2 mM L‐glutamate, and penicillin/streptomycin at 37°C in humidified 95% air and 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

miR‐17‐92 cluster‐BTG2 axis regulates B‐cell receptor signaling in mantle cell lymphoma

Kawaji‐Kanayama,

Tsukamoto,

Nakano

et al. 2023

Cancer Science

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B‐cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR‐17‐92 cluster remains unclear although the oncogenic microRNA (miRNA) miR‐17‐92 cluster is highly expressed in patients with MCL. We revealed that miR‐17‐92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR‐17‐92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. To comprehensively identify miR‐17‐92 cluster target genes, we performed pulldown‐seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead‐coated streptavidin, and quantified using next‐generation sequencing. The pulldown‐seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR‐19b), CDKN2A (miR‐17), SYNE1 (miR‐20a), TET2 (miR‐18, miR‐19b, and miR‐92a), TNFRSF10A (miR‐92a), and TRAF3 (miR‐17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR‐17‐92 cluster‐activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL.

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Establishment and Characteristics of a Novel Mantle Cell Lymphoma-derived Cell Line and a Bendamustine-resistant Subline

Abstract: BH resistance is mediated by overlapping mechanisms with overexpression of ABCB1 and MGST1, and is potentially accompanied by multidrug resistance in MCL.

Cited by 7 publications

References 30 publications

Methylation of PLK-1 Potentially Drives Bendamustine Resistance in Leukemia Cells

Methylation of PLK-1 Potentially Drives Bendamustine Resistance in Leukemia Cells

Bruton’s Tyrosine Kinase Inhibitor Zanubrutinib Effectively Modulates Cancer Resistance by Inhibiting Anthracycline Metabolism and Efflux

miR‐17‐92 cluster‐BTG2 axis regulates B‐cell receptor signaling in mantle cell lymphoma

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