DNMT1 is associated with cell cycle and DNA replication gene sets in diffuse large B-cell lymphoma

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the role of SYK in its pathogenesis is not completely understood. Using tissue microarray, we demonstrated for the first time that SYK protein is activated in 27 of 61 (44%) primary human DLBCL tissues. Among DLBCL cell lines, 7 were sensitive and 3 were resistant to a highly specific SYK inhibitor, PRT060318. In sensitive DLBCL cells, SYK inhibition blocked the G1-S transition and caused cell-cycle arrest. This effect was reproduced by genetic reduction of SYK using siRNA. A detailed analysis of the BCR signaling pathways revealed that the consequence of SYK inhibition on PLCγ2 and AKT, as opposed to ERK1/2, was responsible for cell-cycle arrest. Genetic knock-down of these key molecules decelerated the proliferation of lymphoma cells. In addition, BCR signaling can be blocked by PRT060318 in primary lymphoma cells. Together, these findings provide insights into cellular pathways required for lymphoma cell growth and support the rationale for considering SYK inhibition as a potentially useful therapy for DLBCL. The results further suggest the possibility of using PLCγ2 and AKT as biomarkers to predict therapeutic response in prospective clinical trials of specific SYK inhibitors.

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Genetic and epigenetic determinants of diffuse large B-cell lymphoma

Blood Cancer Journal ◽

10.1038/s41408-020-00389-w ◽

2020 ◽

Vol 10 (12) ◽

Author(s):

Tanner J. Bakhshi ◽

Philippe T. Georgel

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Genetic Damage ◽

Cellular Functions ◽

Post Translational Modifications ◽

Development Of Resistance ◽

Large B Cell Lymphoma ◽

Gene Sets ◽

Large B Cell

AbstractDiffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma and is notorious for its heterogeneity, aggressive nature, and the frequent development of resistance and/or relapse after treatment with standard chemotherapy. To address these problems, a strong emphasis has been placed on researching the molecular origins and mechanisms of DLBCL to develop effective treatments. One of the major insights produced by such research is that DLBCL almost always stems from genetic damage that occurs during the germinal center (GC) reaction, which is required for the production of high-affinity antibodies. Indeed, there is significant overlap between the mechanisms that govern the GC reaction and those that drive the progression of DLBCL. A second important insight is that some of the most frequent genetic mutations that occur in DLBCL are those related to chromatin and epigenetics, especially those related to proteins that “write” histone post-translational modifications (PTMs). Mutation or deletion of these epigenetic writers often renders cells unable to epigenetically “switch on” critical gene sets that are required to exit the GC reaction, differentiate, repair DNA, and other essential cellular functions. Failure to activate these genes locks cells into a genotoxic state that is conducive to oncogenesis and/or relapse.

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A novel silicone derivative of natural osalmid (DCZ0858) induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma via the JAK2/STAT3 pathway

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-0123-0 ◽

2020 ◽

Vol 5 (1) ◽

Cited By ~ 3

Author(s):

Kang Lu ◽

Bo Li ◽

Hui Zhang ◽

Zhijian Xu ◽

Dongliang Song ◽

...

Keyword(s):

Cell Cycle ◽

B Cell ◽

Cell Cycle Arrest ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Stat3 Pathway ◽

Cycle Arrest ◽

Large B Cell Lymphoma ◽

Large B Cell

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An Orally Available Small Molecule BCL6 Inhibitor Effectively Suppresses Diffuse Large B Cell Lymphoma Cells Growth in Vitro and in Vivo

10.21203/rs.3.rs-820765/v1 ◽

2021 ◽

Author(s):

Yajing Xing ◽

Weikai Guo ◽

Min Wu ◽

Jiuqing Xie ◽

Dongxia Huang ◽

...

Keyword(s):

Cell Cycle ◽

B Cell ◽

Small Molecule ◽

Target Genes ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background: The transcription factor B cell lymphoma 6 (BCL6) is an oncogenic driver of diffuse large B cell lymphoma (DLBCL) and mediates lymphomagenesis through transcriptional repression of its target genes by recruiting corepressors to its N-terminal broad-complex/tramtrack/bric-a-brac (BTB) domain. Blocking the protein-protein interactions of BCL6 and its corepressors has been proposed as an effective approach for the treatment of DLBCL. However, BCL6 inhibitors with excellent drug-like properties are rare. Hence, the development of BCL6 inhibitors is worth pursuing. Methods: We screened our internal chemical library by luciferase reporter assay and Homogenous Time Resolved Fluorescence (HTRF) assay and a small molecule compound named WK500B was identified. The binding affinity between WK500B and BCL6 was evaluated by surface plasmon resonance (SPR) assay and the binding mode of WK500B and BCL6 was predicted by molecular docking. The function evaluation and anti-cancer activity of WK500B in vitro and in vivo was detected by immunofluorescence assay, Real-Time Quantitative PCR, cell proliferation assay, cell cycle assay, cell apoptosis assay, enzyme-linked immunosorbent assay (ELISA), germinal centre (GC) formation mouse model and mouse xenograft model. Results: WK500B engaged BCL6 inside cells, blocked BCL6 repression complexes, reactivated BCL6 target genes, killed DLBCL cells and caused apoptosis as well as cell cycle arrest. In animal models, WK500B inhibited germinal centre formation and DLBCL tumor growth without toxic and side effects. Moreover, WK500B showed favourable pharmacokinetics and presented superior druggability compared to other BCL6 inhibitors. Conclusions: WK500B showed strong efficacy and favourable pharmacokinetics and presented superior druggability compared to other BCL6 inhibitors. So, WK500B is a promising candidate that could be developed as an effective orally available therapeutic agent for DLBCL.

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