A Dual TLR7/TLR9 Inhibitor HJ901 Inhibits ABC-DLBCL Expressing the MyD88 L265P Mutation

An, Beiying; Zhu, Shan; Li, Tete; Wu, Jing; Zang, Guoxia; Lv, Xinping; Qiao, Yuan; Huang, Jing; Shao, Yan; Cui, Jiuwei; Liu, Yongjun; Chen, Jingtao

doi:10.3389/fcell.2020.00262

Cited by 6 publications

(6 citation statements)

References 44 publications

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“…However, in DLBCL NETs promote the survival of malignant B cells via TLR9-dependent manner [ 82 ]. In line with this observation the TLR9 antagonist was shown to be effective in reducing the growth of B-cell lymphoma [ 83 ].…”

Section: Defects In Neutrophils’ Functions and Their Influence On Immune Response Development In Cll And Dlbclmentioning

confidence: 79%

The Role of Neutrophils in the Pathogenesis of Chronic Lymphocytic Leukemia

Wachowska

Wojciechowska

Muchowicz

2021

IJMS

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Tumor-associated neutrophils appear to be a crucial element of the tumor microenvironment that actively participates in the development and progression of cancerous diseases. The increased lifespan, plasticity in changing of phenotype, and functions of neutrophils influence the course of the disease and may significantly affect survival. In patients with chronic lymphocytic leukemia (CLL), disturbances in neutrophils functions impede the effective immune defense against pathogens. Therefore, understanding the mechanism underlying such a phenomenon in CLL seems to be of great importance. Here we discuss the recent reports analyzing the phenotype and functions of neutrophils in CLL, the most common leukemia in adults. We summarize the data concerning both the phenotype and the mechanisms by which neutrophils directly support the proliferation and survival of malignant B cells.

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Section: Defects In Neutrophils’ Functions and Their Influence On Immune Response Development In Cll And Dlbclmentioning

confidence: 79%

The Role of Neutrophils in the Pathogenesis of Chronic Lymphocytic Leukemia

Wachowska

Wojciechowska

Muchowicz

2021

IJMS

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“…PI3K/AKT/mTOR pathway involved in crucial functions such as cellular proliferation, cell cycle regulation, and cell motility in DLBCL [ 21 ]. JAK-STAT signaling pathways were associated with pathogenesis of ABC-DLBCL [ 22 ]. DLBCL patients with the NOTCH1 mutations have worse PFS and OS [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of CXCR4 Upregulation in Diffuse Large B-Cell Lymphoma Associated with Prognostic Significance and Clinicopathological Characteristics

et al. 2022

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Background. Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous malignant lymphoma with distinct characteristics. Patients with treatment failure after the standard immunochemotherapy have worse prognosis, which implies the necessity to uncover novel targets. The C-X-C chemokine receptor 4 (CXCR4) overexpression has been identified in several hematopoietic malignancies. However, the expression signatures and prognostic significance of CXCR4 in DLBCL associated with clinicopathological features remain unclear. Methods. Gene expression profiles of DLBCL were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Then, a meta-analysis with an integrated bioinformatic analysis was performed to assess the relationship between CXCR4 expression and clinicopathological features of DLBCL. Finally, experimental verification including immunohistochemical (IHC) staining and real-time quantitative PCR (qPCR) was carried out using patient samples. In vitro cell line viability tests were conducted using CXCR4 inhibitor WZ811. Results. DLBCL patients with activated B-cell-like (ABC) subtype have higher expression level of CXCR4 with worse survival. Differential expressed genes in the CXCR4-upregulation group were enriched in canonical pathways associated with oncogenesis. DLBCL with CXCR4 upregulation had lower degree of CD8+ T cell infiltration. TIMER analysis demonstrated that the CXCR4 expression was positively correlated with the expression of CD5, MYC, NOTCH1, PDCD1, CD274, mTOR, FOXO1, and hnRNPA2B1 in DLBCL. IHC study in patient samples showed the positive correlation between CXCR4 and nongerminal center B-cell (non-GCB) subtype and mTOR expression. Meanwhile, quantitative polymerase chain reaction results revealed that high CXCR4 mRNA level was correlated to double-hit DLBCL. Finally, cell viability test showed that WZ811 exerted antiproliferation effect in DLBCL cell lines in a dose-dependent manner. Conclusion. CXCR4 was upregulated in ABC-DLBCL associated with worse prognosis. Our analysis predicted CXCR4 as a potential target for DLBCL treatment, which may serve as an inhibitor both on BCR signaling and nuclear export warranting further investigation in clinical trials.

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“…The connection between enhanced TLR expression and hematopoietic malignancies indicates there are therapeutic benefits from TLR signaling repression. Various novel TLR pathway inhibitors emerge, such as HJ901 (TLR7/9 inhibitor) [ 107 ] and CA-4948 (IRAK4 inhibitor) [ 108 ]. They are becoming the therapeutic targets for the treatment of MDS, AML, ABC-DLBCL, and non-Hodgkin’s lymphoma, among other diseases.…”

Section: Toll-like Receptors and Hematologymentioning

confidence: 99%

The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies

et al. 2023

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Toll-like receptors (TLR) belong to the pattern recognition receptors (PRR). TLR7 and the closely correlated TLR8 affiliate with toll-like receptors family, are located in endosomes. They recognize single-stranded ribonucleic acid (RNA) molecules and synthetic deoxyribonucleic acid (DNA)/RNA analogs—oligoribonucleotides. TLRs are primarily expressed in hematopoietic cells. There is compiling evidence implying that TLRs also direct the formation of blood cellular components and make a contribution to the pathogenesis of certain hematopoietic malignancies. The latest research shows a positive effect of therapy with TRL agonists on the course of hemato-oncological diseases. Ligands impact activation of antigen-presenting cells which results in production of cytokines, transfer of mentioned cells to the lymphoid tissue and co-stimulatory surface molecules expression required for T-cell activation. Toll-like receptor agonists have already been used in oncology especially in the treatment of dermatological neoplastic lesions. The usage of these substances in the treatment of solid tumors is being investigated. The present review discusses the direct and indirect influence that TLR7/8 agonists, such as imiquimod, imidazoquinolines and resiquimod have on neoplastic cells and their promising role as adjuvants in anticancer vaccines.

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A Dual TLR7/TLR9 Inhibitor HJ901 Inhibits ABC-DLBCL Expressing the MyD88 L265P Mutation

Cited by 6 publications

References 44 publications

The Role of Neutrophils in the Pathogenesis of Chronic Lymphocytic Leukemia

The Role of Neutrophils in the Pathogenesis of Chronic Lymphocytic Leukemia

Identification of CXCR4 Upregulation in Diffuse Large B-Cell Lymphoma Associated with Prognostic Significance and Clinicopathological Characteristics

The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies

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