Identification BCL6 and miR-30 family associating with Ibrutinib resistance in activated B-cell-like diffuse large B-cell lymphoma

Li, Jiazheng; Huang, Yan; Zhang, Yun; Wen, Junping; Chen, Yanxin; Wang, Lingyan; Jiang, Peifang; Hu, Jianda

doi:10.1007/s12032-021-01470-5

Cited by 11 publications

(8 citation statements)

References 58 publications

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“…By GEO2R ( Liu et al, 2019 ), P < 0.01, Log FC > 2 or Log FC < -2 were defined as screening criteria. Next, Metascape 4 ( Liu et al, 2020 ), KEGG 5 ( Zheng et al, 2021 ), and DAVID 6 ( Li J. et al, 2021 ) databases were used to analyze biological process (BP), cellular component (CC), molecular function (MF) and related pathways of differentially expressed mRNAs (DEmRNAs).…”

Section: Methodsmentioning

confidence: 99%

Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis

Liu

Chen

et al. 2021

Front. Cell Dev. Biol.

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BackgroundTumor microenvironment (TME) plays important roles in different cancers. Our study aimed to identify molecules with significant prognostic values and construct a relevant Nomogram, immune model, competing endogenous RNA (ceRNA) in lung adenocarcinoma (LUAD).Methods“GEO2R,” “limma” R packages were used to identify all differentially expressed mRNAs from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Genes with P-value <0.01, LogFC>2 or <-2 were included for further analyses. The function analysis of 250 overlapping mRNAs was shown by DAVID and Metascape software. By UALCAN, Oncomine and R packages, we explored the expression levels, survival analyses of CDK2 in 33 cancers. “Survival,” “survminer,” “rms” R packages were used to construct a Nomogram model of age, gender, stage, T, M, N. Univariate and multivariate Cox regression were used to establish prognosis-related immune forecast model in LUAD. CeRNA network was constructed by various online databases. The Genomics of Drug Sensitivity in Cancer (GDSC) database was used to explore correlations between CDK2 expression and IC50 of anti-tumor drugs.ResultsA total of 250 differentially expressed genes (DEGs) were identified to participate in many cancer-related pathways, such as activation of immune response, cell adhesion, migration, P13K-AKT signaling pathway. The target molecule CDK2 had prognostic value for the survival of patients in LUAD (P = 5.8e-15). Through Oncomine, TIMER, UALCAN, PrognoScan databases, the expression level of CDK2 in LUAD was higher than normal tissues. Pan-cancer analysis revealed that the expression, stage and survival of CDK2 in 33 cancers, which were statistically significant. Through TISIDB database, we selected 13 immunodepressants, 21 immunostimulants associated with CDK2 and explored 48 genes related to these 34 immunomodulators in cBioProtal database (P < 0.05). Gene Set Enrichment Analysis (GSEA) and Metascape indicated that 49 mRNAs were involved in PUJANA ATM PCC NETWORK (ES = 0.557, P = 0, FDR = 0), SIGNAL TRANSDUCTION (ES = –0.459, P = 0, FDR = 0), immune system process, cell proliferation. Forest map and Nomogram model showed the prognosis of patients with LUAD (Log-Rank = 1.399e-08, Concordance Index = 0.7). Cox regression showed that four mRNAs (SIT1, SNAI3, ASB2, and CDK2) were used to construct the forecast model to predict the prognosis of patients (P < 0.05). LUAD patients were divided into two different risk groups (low and high) had a statistical significance (P = 6.223e-04). By “survival ROC” R package, the total risk score of this prognostic model was AUC = 0.729 (SIT1 = 0.484, SNAI3 = 0.485, ASB2 = 0.267, CDK2 = 0.579). CytoHubba selected ceRNA mechanism medicated by potential biomarkers, 6 lncRNAs-7miRNAs-CDK2. The expression of CDK2 was associated with IC50 of 89 antitumor drugs, and we showed the top 20 drugs with P < 0.05.ConclusionIn conclusion, our study identified CDK2 related immune forecast model, Nomogram model, forest map, ceRNA network, IC50 of anti-tumor drugs, to predict the prognosis and guide targeted therapy for LUAD patients.

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Section: Methodsmentioning

confidence: 99%

Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis

Liu

Chen

et al. 2021

Front. Cell Dev. Biol.

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“…Therefore, tumor resistance urgently needs to be addressed . In addition to being directly involved in the occurrence and development of tumors, BCL6 also widely mediates drug resistance. , BCL6 is significantly upregulated in chronic myeloid leukemia (CML) cells or Ph + acute lymphoblastic leukemia (Ph + ALL) cells after treatment with tyrosine kinase inhibitors (TKIs), which causes a resistance to TKIs. , Studies have reported that BCL6 is associated with resistance to TKIs in CML or ALL. , Meanwhile, BCL6 was critical for both stem cell survival in CML and cell self-renewal in CML or Ph + ALL. , Moreover, a novel mechanism of drug resistance based on the protective feedback signal of leukemia cells to TKIs was reported, and BCL6 was a central component of the drug-resistance pathway; drug-resistant as well as leukemia-initiating subclones can be eradicated by targeting BCL6 . In addition, the combination of BCL6 inhibitors and BCL2 inhibitors was effective in overcoming the inherent resistance of BCL2 inhibitors .…”

Section: The Pivotal Roles Of Bcl6 In Cancer Developmentmentioning

confidence: 99%

“…More efficient antitumor potential was observed in GCB-DLBCL and ABC-DLCBL cell lines with the combination of 7 and doxorubicin. Furthermore, BCL6 was an important gene involved in the resistance of ABC-DLBCL cells to Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, and 7 could efficiently decrease resistance …”

Section: Recent Developments In Bcl6 Inhibitorsmentioning

confidence: 99%

B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas

et al. 2022

J. Med. Chem.

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B-cell lymphoma 6 (BCL6) is a transcriptional repressor that regulates the differentiation of B lymphocytes and mediates the formation of germinal centers (GCs) by recruiting corepressors through the BTB domain of BCL6. Physiological processes regulated by BCL6 involve cell activation, differentiation, DNA damage, and apoptosis. BCL6 is highly expressed when the gene is mutated, leading to the malignant proliferation of cells and drives tumorigenesis. BCL6 overexpression is closely correlated with tumorigenesis in diffuse large B-cell lymphoma (DLBCL) and other lymphomas, and BCL6 inhibitors can effectively inhibit some lymphomas and overcome resistance. Therefore, targeting BCL6 might be a promising therapeutic strategy for treating lymphomas. Herein, we comprehensively review the latest development of BCL6 inhibitors in diffuse large B-cell lymphoma and discuss the overview of the pharmacophores of BCL6 inhibitors and their efficacies in vitro and in vivo. Additionally, the current advances in BCL6 degraders are provided.

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“…(3) Cell cycle defects: CCND1 mutations cause an increase in CCND1 protein levels through a proteolytic defect mechanism that leads to ibrutinib resistance 55 . (4) Upregulation of gene expression: BCL6 , IRF4 , CD80 , and PRDM1 are the common target genes of miR‐30 56 . BCL6 is overexpressed in patients who are unresponsive to ibrutinib.…”

Section: De‐regulated Pathways Associated With Btki Resistancementioning

confidence: 99%

“… 55 (4) Upregulation of gene expression: BCL6 , IRF4 , CD80 , and PRDM1 are the common target genes of miR‐30. 56 BCL6 is overexpressed in patients who are unresponsive to ibrutinib. FX1 (a BCL6 inhibitor) can enhance the sensitivity of BTK C481S HBL‐1 cells.…”

Section: De‐regulated Pathways Associated With Btki Resistancementioning

confidence: 99%

The resistance mechanisms and treatment strategies of BTK inhibitors in B‐cell lymphoma

Wang

Zhang

Yang

et al. 2021

Hematological Oncology

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Bruton's tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of B-cell lymphoma (BCL). These drugs interfere with the mechanisms underlying malignant Bcell pathophysiology, allowing better drug response as well as low toxicity. However, these multiple mechanisms also lead to drug resistance, which compromised the treatment outcome and needs to be solved urgently. This review focuses on genomic variations (such as BTK and its downstream PCLG2 mutations as well as Del 8p, 2p+, Del 6q/8p, BIRC3, TRAF2, TRAF3, CARD11, MYD88, and CCND1 mutations) and related pathways (such as PI3K/Akt/mTOR, NF-κB, MAPK signaling pathways, overexpression of B-cell lymphoma 6, platelet-derived growth factor, toll-like receptors, and microenvironment, cancer stem cells, and exosomes) involved in cancer pathophysiology to discuss the mechanisms underlying resistance to BTKi. We have also reviewed the newly reported drug resistance mechanisms and the proposed potential treatment strategies (the next-generation BTKi, proteolysis-targeting chimera-BTK, XMU-MP-3, PI3K-Akt-mTOR pathway, MYC or LYN kinase inhibitor, and other small-molecule targeted drugs) to overcome drug resistance. The findings presented in this review lay a strong foundation for further research in this field.

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Identification BCL6 and miR-30 family associating with Ibrutinib resistance in activated B-cell-like diffuse large B-cell lymphoma

Cited by 11 publications

References 58 publications

Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis

Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis

B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas

The resistance mechanisms and treatment strategies of BTK inhibitors in B‐cell lymphoma

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