Dysregulated MDR1 by PRDM1/Blimp1 Is Involved in the Doxorubicin Resistance of Non-Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma

Qing, Kai; Jin, Zhen; Xu, Zhuang; Wang, Wenfang; Li, Xiaoyang; Zhang, Yunxiang; Wang, Lining; Zhu, Hongming; Xiang, Rufang; Wu, Shishuang; Li, Ran; Jiang, Ge; Xue, Kai; Li, Junmin

doi:10.1159/000520070

Cited by 3 publications

(3 citation statements)

References 40 publications

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“…FARAGE and SU-DHL-2 cells were exposed to incremental doses (0.0035, 0.035, and 0.35 μM) of DOX (Sigma-Aldrich, Merck KGaA, Darmstadt, Germany). The DOX-resistant cells FARAGE/DOX and SU-DHL-2/DOX were established when they could stably grow under 0.35 μM DOX treatment 14 .…”

Section: Methodsmentioning

confidence: 99%

FOXP1-GINS1 axis promotes DLBCL proliferation and directs doxorubicin resistance

Chen¹,

Wang²,

Cui³

et al. 2023

J. Cancer

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GINS1 is overexpressed in several types of cancers including leukemia and linked to poor outcomes. However, GINS1 remains poorly investigated in DLBCL (diffuse large B-cell lymphoma). This project aimed to explore the expression, functions and regulation of GINS1 in DLBCL. In this study, through analysis of clinical specimens from DLBCL patients, we uncovered that GINS1 was upregulated in DLBCL. By EMSA, ChIP and luciferase reporter assays, it was found that FOXP1 transcriptionally activated GINS1 expression by directly binding to the promoter region of the GINS1 gene. Western blotting and RT-PCR also revealed that GINS1 expression positively correlated with FOXP1 in human DLBCL specimens and cell lines. In an in vivo xenograft lymphoma mouse model, the FOXP1/GINS1 regulatory axis was also validated. Moreover, with CCK8 cell proliferation assays and colony formation assay, elevated GINS1 expression was found to be associated with doxorubicin resistance in lymphoma cells. Our findings showed that the FOXP1-GINS1 axis played a critical role in DLBCL development and doxorubicin resistance, and targeting the FOXP1-GINS1 axis could be a potential therapeutic approach for DLBCL treatment.

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Section: Methodsmentioning

confidence: 99%

FOXP1-GINS1 axis promotes DLBCL proliferation and directs doxorubicin resistance

Chen¹,

Wang²,

Cui³

et al. 2023

J. Cancer

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“…Loss of BLIMP1 function contributes to the overall poor prognosis of ABC-DLBCL patients [ 316 , 317 ]. Furthermore, dysregulated multidrug resistance protein 1 (MDR1; ABCB1) by BLIMP1 is involved in the doxorubicin resistance of non-GC B-cell-like DLBCL [ 318 ].…”

Section: Exosomal Micrornas In the Pathogenesis Of Dlbclmentioning

confidence: 99%

Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma

Melnik

Stadler

Weiskirchen

et al. 2023

IJMS

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Epidemiological evidence supports an association between cow’s milk consumption and the risk of diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma worldwide. This narrative review intends to elucidate the potential impact of milk-related agents, predominantly milk-derived exosomes (MDEs) and their microRNAs (miRs) in lymphomagenesis. Upregulation of PI3K-AKT-mTORC1 signaling is a common feature of DLBCL. Increased expression of B cell lymphoma 6 (BCL6) and suppression of B lymphocyte-induced maturation protein 1 (BLIMP1)/PR domain-containing protein 1 (PRDM1) are crucial pathological deviations in DLBCL. Translational evidence indicates that during the breastfeeding period, human MDE miRs support B cell proliferation via epigenetic upregulation of BCL6 (via miR-148a-3p-mediated suppression of DNA methyltransferase 1 (DNMT1) and miR-155-5p/miR-29b-5p-mediated suppression of activation-induced cytidine deaminase (AICDA) and suppression of BLIMP1 (via MDE let-7-5p/miR-125b-5p-targeting of PRDM1). After weaning with the physiological termination of MDE miR signaling, the infant’s BCL6 expression and B cell proliferation declines, whereas BLIMP1-mediated B cell maturation for adequate own antibody production rises. Because human and bovine MDE miRs share identical nucleotide sequences, the consumption of pasteurized cow’s milk in adults with the continued transfer of bioactive bovine MDE miRs may de-differentiate B cells back to the neonatal “proliferation-dominated” B cell phenotype maintaining an increased BLC6/BLIMP1 ratio. Persistent milk-induced epigenetic dysregulation of BCL6 and BLIMP1 expression may thus represent a novel driving mechanism in B cell lymphomagenesis. Bovine MDEs and their miR cargo have to be considered potential pathogens that should be removed from the human food chain.

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“…Brentuximab vedotin-refractory HL, patients were found to have upregulation of the multidrug resistance MDR1 gene [180]. The expression of ABC transporters is increased also in DLBCL cells, where it correlates with a worse response to treatment [181].…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

Molecular Aspects of Resistance to Immunotherapies—Advances in Understanding and Management of Diffuse Large B-Cell Lymphoma

Kusowska

Kubacz

Krawczyk

et al. 2022

IJMS

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Despite the unquestionable success achieved by rituximab-based regimens in the management of diffuse large B-cell lymphoma (DLBCL), the high incidence of relapsed/refractory disease still remains a challenge. The widespread clinical use of chemo-immunotherapy demonstrated that it invariably leads to the induction of resistance; however, the molecular mechanisms underlying this phenomenon remain unclear. Rituximab-mediated therapeutic effect primarily relies on complement-dependent cytotoxicity and antibody-dependent cell cytotoxicity, and their outcome is often compromised following the development of resistance. Factors involved include inherent genetic characteristics and rituximab-induced changes in effectors cells, the role of ligand/receptor interactions between target and effector cells, and the tumor microenvironment. This review focuses on summarizing the emerging advances in the understanding of the molecular basis responsible for the resistance induced by various forms of immunotherapy used in DLBCL. We outline available models of resistance and delineate solutions that may improve the efficacy of standard therapeutic protocols, which might be essential for the rational design of novel therapeutic regimens.

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Dysregulated MDR1 by PRDM1/Blimp1 Is Involved in the Doxorubicin Resistance of Non-Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma

Cited by 3 publications

References 40 publications

FOXP1-GINS1 axis promotes DLBCL proliferation and directs doxorubicin resistance

FOXP1-GINS1 axis promotes DLBCL proliferation and directs doxorubicin resistance

Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma

Molecular Aspects of Resistance to Immunotherapies—Advances in Understanding and Management of Diffuse Large B-Cell Lymphoma

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