BCL6, a key oncogene, in the placenta, pre-eclampsia and endometriosis

Human Reproduction Update, Год журнала: 2022, Номер 28(6), С. 890 - 909

Опубликована: Май 31, 2022

Abstract BACKGROUND The key oncogene B-cell lymphoma 6 (BCL6) drives malignant progression by promoting proliferation, overriding DNA damage checkpoints and blocking cell terminal differentiation. However, its functions in the placenta endometrium remain to be defined. OBJECTIVE AND RATIONALE Recent studies provide evidence that BCL6 may play various roles human endometrium. Deregulated might related pathogenesis of pre-eclampsia (PE) as well endometriosis. In this narrative review, we aimed summarize current knowledge regarding pathophysiological role these two reproductive organs, discuss molecular mechanisms, underline associated research perspectives. SEARCH METHODS We conducted a comprehensive literature search using PubMed for human, animal cellular published until October 2021 following areas: placenta, PE endometriosis, combination with fusion, migration, invasion, differentiation, stem/progenitor maintenance lineage commitment. OUTCOMES data demonstrate is important survival, migration invasion trophoblastic cells. have critical survival differentiation aberrantly upregulated pre-eclamptic placentas endometriotic lesions through including changes gene transcription mRNA translation post-transcriptional/translational modifications. Importantly, increased endometrial considered non-invasive diagnostic marker endometriosis predictor poor outcomes IVF. These highlight crucial placental development homeostasis, upregulation PE, infertility. WIDER IMPLICATIONS lesson learned from reinforces notion numerous signaling pathways regulators are shared tumors organs. Their alteration promote malignancies gestational disorders.

Язык: Английский

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B-cell Lymphoma 6 (BCL6): From Master Regulator of Humoral Immunity to Oncogenic Driver in Pediatric Cancers

Molecular Cancer Research, Год журнала: 2022, Номер 20(12), С. 1711 - 1723

Опубликована: Сен. 27, 2022

Abstract B-cell lymphoma 6 (BCL6) is a protooncogene in adult and pediatric cancers, first identified diffuse large (DLBCL) where it acts as repressor of the tumor suppressor TP53, conferring survival, protection, maintenance cells. BCL6 expression normal B cells fundamental regulation humoral immunity, via initiation germinal centers (GC). Its role during production high affinity immunoglobins (that recognize bind specific antigens) believed to underpin its function an oncogene. known drive self-renewal capacity leukemia-initiating (LIC), with acute lymphoblastic leukemia (ALL), myeloid (AML), glioblastoma (GBM) associated disease progression treatment resistance. The mechanisms underpinning BCL6-driven therapy resistance are yet be uncovered; however, activity considered confer poor prognosis clinical setting. BCL6’s key binding partner, corepressor (BCOR), frequently mutated cancers appears act concert BCL6. Using publicly available data, here we show that ubiquitously overexpressed brain tumors, inversely BCOR, highlighting potential for targeting these often lethal untreatable cancers. In this review, summarize what (role, effect, mechanisms) two sides function, tumorigenesis, well review inhibitors highlight areas opportunity improve outcomes patients cancer.

Язык: Английский

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Co-expression of a PD-L1-specific chimeric switch receptor augments the efficacy and persistence of CAR T cells via the CD70-CD27 axis

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Окт. 13, 2022

Abstract Co-expression of chimeric switch receptors (CSRs) specific for PD-L1 improves the antitumor effects antigen receptor (CAR) T cells. However, trans-recognition between CSRs and expressed by activated CAR cells remain unclear. Here, we design a CSR (CARP), containing transmembrane cytoplasmic signaling domains CD28 but not CD3 ζ chain. We show that CARP enhance activity anti-mesothelin (CARMz) in vitro vivo. In addition, confocal microscopy indicates molecules on CARMz accumulate at cell-cell contacts with Using single-cell RNA-sequencing analysis, reveal promote differentiation into central memory-like cells, upregulate genes related to Th1 downregulate Th2-associated cytokines through CD70-CD27 axis. Moreover, these are restricted PD-L1, as CAR19 expressing anti-CD19 exhibit similar anti-PSCA truncated CD19 expression. These findings suggest target may improve efficacy persistence via

Язык: Английский

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BCL6 is regulated by the MAPK/ELK1 axis and promotes KRAS-driven lung cancer

Journal of Clinical Investigation, Год журнала: 2022, Номер 132(22)

Опубликована: Ноя. 14, 2022

Mutational activation of KRAS is a common oncogenic event in lung cancer, yet effective therapies are still lacking. Here, we identify B cell lymphoma 6 (BCL6) as lynchpin KRAS-driven cancer. BCL6 expression was increased upon tumor tissue mice and positively correlated with the KRAS-GTP, active form KRAS, various human cancer lines. Moreover, highly expressed KRAS-mutant adenocarcinomas associated poor patient survival. Mechanistically, MAPK/ERK/ELK1 signaling axis downstream mutant directly regulated expression. maintained global prereplication complex components; therefore, inhibition induced stalling replication fork, leading to DNA damage growth arrest cells. Importantly, BCL6-specific knockout lungs significantly reduced burden mortality LSL-KrasG12D/+ mouse model. Likewise, pharmacological impeded cells both vitro vivo. In summary, our findings reveal crucial role promoting KRAS-addicted suggest therapeutic target for treatment this intractable disease.

Язык: Английский

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B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(20), С. 10968 - 10968

Опубликована: Окт. 11, 2024

B cell lymphoma 6 (BCL6) is a conserved multi-domain protein that functions principally as transcriptional repressor. This regulates many pivotal aspects of immune development and function. BCL6 critical for germinal center (GC) formation the high-affinity antibodies, with key roles in generation function GC cells, follicular helper T (Tfh) regulatory (Tfr) various memory cells. also controls macrophage production well performing myriad additional outside system. Many these are throughout evolution. The

Язык: Английский

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BCL6 Alleviates Hepatic Ischemia/Reperfusion Injury Via Recruiting SIRT1 to Repress the NF-κB/NLRP3 Pathway

Transplantation, Год журнала: 2025, Номер unknown

Опубликована: Янв. 13, 2025

Background. Hepatic ischemia/reperfusion (I/R) injury (HIRI) is an intrinsic phenomenon observed in the process of various liver surgeries. Unfortunately, there are currently few options available to prevent HIRI. Accordingly, we aim explore role and key downstream effects B-cell lymphoma 6 (BCL6) hepatic I/R (HIR). Methods. BCL6 expression levels were measured tissue primary hepatocytes stimulated by hypoxia/reoxygenation (H/R). Moreover, ascertained effect on HIR vivo using liver-specific knockout mice adenovirus-BCL6-infected mice. RNA-sequencing, luciferase, chromatin immunoprecipitation, interactome analysis combined identify direct target corresponding molecular events contributing function. DNA pull-down was applied upstream H/R challenge. Results. represses vitro. overexpression attenuates inflammation apoptosis after injury, whereas deficiency aggravates I/R-induced injury. RNA-sequencing showed that modulated nucleotide-binding oligomerization domain, leucine-rich repeat pyrin domain-containing 3 inflammasome signaling Mechanistically, deacetylated nuclear factor kappa-B p65 lysine 310 recruiting sirtuin 1 (SIRT1), thereby inhibiting kappa-B/nucleotide-binding pathway. SIRT1 blocked detrimental depletion. EX 527, a inhibitor, vanished protection from overexpression. Furthermore, transcription 7 found mediate regulation Conclusions. Our results provide first evidence supporting as important protective agent HIR. This suggests potential therapeutic approach for

Язык: Английский

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Roles of B-cell lymphoma 6 in orthodontic tooth movement of rat molars

European Journal of Orthodontics, Год журнала: 2025, Номер 47(2)

Опубликована: Янв. 26, 2025

B-cell lymphoma 6 (Bcl6) inhibits osteoclast differentiation in vitro; however, its role orthodontic tooth movement (OTM) remains unclear. This study aimed to investigate the of Bcl6 OTM rat molars. was performed on maxillary first molars male rats using nickel-titanium coil springs (25 gf) for 14 days with or without local injection FX1 (50 mg/kg), a inhibitor (n = 10 per group). Micro-computed tomography (CT) images were used analyse distance and bone morphometric parameters. Immunohistochemistry (IHC) determined expression tartrate-resistant acid phosphatase staining (TRAP) assessed differentiation. TRAP staining, reverse transcription-quantitative polymerase chain reaction effect (1 μM) vitro The cell proliferation Smad4 periodontal ligament (PDL) cells determined. Administration significantly increased decreased bone/tissue volume compared vehicle treatment. IHC showed that vehicle-OTM group had higher than FX1-OTM group. number osteoclasts compression side enhanced Nfatc1, Dc-stamp, Ctsk mRNA vitro. promotes PDL vivo We evaluated only OTM. may play an important via modulation proliferation.

Язык: Английский

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B-cell lymphoma 6 alleviates nonalcoholic fatty liver disease in mice through suppression of fatty acid transporter CD36

Cell Death and Disease, Год журнала: 2022, Номер 13(4)

Опубликована: Апрель 18, 2022

Abstract Nonalcoholic fatty liver disease (NAFLD) is an ubiquitous that exists across a wide spectrum ranging from steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Hallmarks of NAFLD are lipid accumulation, insulin resistance, chronic low-grade inflammation. However, there currently no medications approved for NAFLD. B-cell lymphoma 6 (BCL6) transcriptional inhibitor vital germinal center formation. Our study identified BCL6 as critical modulator hepatic metabolism appears to contribute the initiation progression In our research, we induced overexpression using adeno-associated virus (AAV), well conditional liver-specific knockout mice (BCL6-CKO). With these models, noted improved resistance steatosis in models maintained on HFD diet. Conversely, parameters worsened livers with downregulated levels. Mechanistically, translocase acid CD36 was determined be target influences its role steatosis. bound directly promoter region, restraining transcription under physiological conditions. We conclude hepatocyte inhibits mice, including deranged accumulation glucose metabolism, through CD36-dependent manner. These results indicate may potentially targeted treatment.

Язык: Английский

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A Novel BRD Family PROTAC Inhibitor dBET1 Exerts Great Anti-Cancer Effects by Targeting c-MYC in Acute Myeloid Leukemia Cells

Pathology & Oncology Research, Год журнала: 2022, Номер 28

Опубликована: Июнь 27, 2022

Acute myeloid leukemia (AML) represents an aggressive hematopoietic malignancy with a prognosis inferior to that of other leukemias. Recent targeted therapies offer new opportunities achieve better treatment outcomes. However, due the complex heterogeneity AML, its remains dismal. In this study, we first identified correlation between high expression BRD4 and overall survival patients AML. Targeted degradation BRD2, BRD3, proteins by dBET1, proteolysis-targeting chimera (PROTAC) against bromodomain extra-terminal domain (BET) family members, showed cytotoxic effects on Kasumi (AML1-ETO), NB4 (PML-RARa), THP-1 (MLL-AF9), MV4-11 (MLL-AF4) AML cell lines representing different molecular subtypes Furthermore, determined dBET1 arrested cycling enhanced apoptosis c-MYC was as downstream target. Collectively, our results indicated had broad anti-cancer lesions provided more benefits

Язык: Английский

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Targeting BCL6 in Gastrointestinal Stromal Tumor Promotes p53-Mediated Apoptosis to Enhance the Antitumor Activity of Imatinib

Cancer Research, Год журнала: 2023, Номер 83(21), С. 3624 - 3635

Опубликована: Авг. 9, 2023

Imatinib mesylate (IM) has revolutionized the treatment of gastrointestinal stromal tumor (GIST). However, most patients inevitably acquire IM resistance. Second- and third-line treatments exhibit modest clinical benefits with a median time to disease progression 4 6 months, highlighting urgency for novel therapeutic approaches. Here, we report that expression BCL6, known oncogenic driver transcriptional repressor, was significantly induced in GIST cells following treatment. Elevated BCL6 levels suppressed apoptosis contributed Mechanistically, recruited SIRT1 TP53 promoter modulate histone acetylation transcriptionally repress expression. The reduction p53 subsequently attenuated cell promoted tolerance IM. Concordantly, showing high inhibitor, BI-3802, conferred sensitivity. Furthermore, BI-3802 showed striking synergy IM-responsive IM-resistant vitro vivo. Thus, these findings reveal role resistance suggest combination inhibitors could be potentially effective GIST.BCL6 drives imatinib by inhibiting p53-mediated can targeted synergistically suppress growth, providing strategy treating tumor.

Язык: Английский

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