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FBXW7 Triggers Degradation of KMT2D to Favor Growth of Diffuse Large B-cell Lymphoma Cells.

ABSTRACT: Mature B-cell neoplasms are the fifth most common neoplasm. Due to significant heterogeneity at the clinical and genetic levels, current therapies for these cancers fail to provide long-term cures. The clinical success of proteasome inhibition for the treatment of multiple myeloma and B-cell lymphomas has made the ubiquitin pathway an important emerging therapeutic target. In this study, we assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. FBXW7 targeted the frequently inactivated tumor suppressor KMT2D for protein degradation, subsequently regulating gene expression signatures related to oxidative phosphorylation (OxPhos). Loss of FBXW7 inhibited diffuse large B-cell lymphoma cell growth and further sensitized cells to OxPhos inhibition. These data elucidate a novel mechanism of regulation of KMT2D levels by the ubiquitin pathway and uncover a role of FBXW7 in regulating oxidative phosphorylation in B-cell malignancies. SIGNIFICANCE: These findings characterize FBXW7 as a prosurvival factor in B-cell lymphoma via degradation of the chromatin modifier KMT2D.

SUBMITTER: Saffie R

PROVIDER: S-EPMC7417195 | biostudies-literature |

REPOSITORIES: biostudies-literature

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<i>KMT2D</i> mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-induced regulatory T cell trafficking via FBXW7-NOTCH-MYC/TGF-β1 axis.

Project description:Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-β1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-β1 axis.

| S-EPMC11302885 | biostudies-literature

Promoting effects of calponin 3 on the growth of diffuse large B‑cell lymphoma cells.

Project description:Diffuse large B‑cell lymphoma (DLBCL) is one of the most common types of lymphoma. Calponin 3 (CNN3) is a thin filament‑associated protein previously known to regulate smooth muscle contraction. Recent evidence illustrates its involvement in carcinogenesis; however, its roles in DLBCL remain unknown. CNN3 was found to be highly expressed in DLBCL specimens according to the online Gene Expression Profiling Interactive Analysis data. The aim of the present study was to investigate the roles of CNN3 in the progression of DLBCL. In vitro, the ectopic expression of CNN3 promoted the proliferation and G1/S transition of DLBCL cells, while its silencing led to opposite alterations. A similar tumor‑promoting role of CNN3 was also demonstrated by injecting nude mice with DLBCL cells over‑ or underexpressing CNN3. The results of dual‑luciferase reporter and chromatin immunoprecipitation assays revealed that forkhead box O3 (FOXO3), a known tumor suppressor in DLBCL, bound to the CNN3 promoter at ‑1955/‑1948 and ‑1190/‑1183, and suppressed the transcription of CNN3. The alterations induced by FOXO3 were partly blocked by CNN3 overexpression. On the whole, the present study demonstrates that CNN3, whose transcriptional activity is negatively regulated by FOXO3, contributes to the malignant behavior of DLBCL cells. The findings of the present study may provide novel diagnostic or therapeutic insight for DLBCL in clinical practice.

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Project description: Not available

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Loss of IRF8 Inhibits the Growth of Diffuse Large B-cell Lymphoma.

Project description:IRF8 is a transcription factor with a critical role in B lymphocyte development and functions. Its role in human diffuse large B-cell lymphoma (DLBCL), however, remained elusive. In this study, using shRNA-mediated knockdown of IRF8 expression, we found that the loss of IRF8 significantly reduced the proliferation of DLBCL cells (P<0.05). Mechanistically, decreasing the levels of IRF8 led to a suppression of the phosphorylation of p38 and ERK, molecules critical for B cell proliferation. Furthermore, using a xenograft lymphoma mouse model, we found that the loss of IRF8 significantly inhibited the growth of lymphomas in vivo (P<0.05). Immunohistochemical analysis of human DLBCL tissues revealed that the levels of IRF8 were significantly greater in non-germinal center B-cell-like (non-GCB) subtype than that in GCB subtype (P<0.05). Analysis of public available data also suggested that the expression levels of IRF8 mRNA in human DLBCL tissues were inversely correlated with patients' overall survival time. Taken together, this study suggested that IRF8 may play an oncogenic role in human DLBCL by promoting cell proliferation.

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BRD4 inhibition sensitizes diffuse large B-cell lymphoma cells to ferroptosis

Project description: Not available

| S-BSST1072 | biostudies-other

Diffuse large B-cell lymphoma

Project description:Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumors. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumors of DLBCL patients, apparently reflecting the variation in tumor proliferation rate, host response and differentiation state of the tumor. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal center B cells ('germinal center B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal center B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumors on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer. This study is described more fully in Alizadeh AA et al.(2000) Nature 403:503-11 Keywords: other

2002-06-27 | GSE60 | GEO

miRNA-425-5p enhances diffuse large B cell lymphoma growth by targeting PTEN

Project description:Background At present, cancer is one of the greatest threats to mankind, and is associated with the highest rates of morbidity and comorbidity. Recently, the advancements in molecular biology have led to an in-depth understanding of the underlying pathophysiology, which may further impact the lead time in the context of early discovery and effective therapy of cancer. Therefore, the present study proposes a better understanding of the role of micro(miR)-425-5p in diffuse large B-cell lymphoma (DLBC). Methods qRT-PCR was carried out to detect the relevant proteins, miRNA and mRNA RNA gene expression in DLBC cells. The effect of miR-425-5p on DLBC growth was examined by CCK-8 and colony formation assays. The binding relationship between genes was verified by dual-luciferase reporter gene assay. Results We demonstrated how the over-expression of miR-425-5p can lead to increased progression of DLBC by increasing the cellular proliferation rate and colony-forming ability. Additionally, we also found that the expression of miR-425-5p could be significantly inhibited on the basis of phosphatase and tensin homolog (PTEN) signaling pathways. Conclusions The present study concludes that miR-425-5p is responsible for the oncogenic progression and relapse of DLBC tumorigenesis via PTEN/PI3K signaling, which can thus be effectively used to achieve better therapeutic outcomes.

| S-EPMC8799000 | biostudies-literature

Diffuse large B-cell lymphoma

2002-06-27 | E-GEOD-60 | biostudies-arrayexpress

Phenotypic Characterization of Diffuse Large B-Cell Lymphoma Cells and Prognostic Impact.

Project description:Multiparameter flow cytometry (MFC) is a fast and cost-effective technique to evaluate the expression of many lymphoid markers in mature B-cell neoplasms, including diffuse large B cell lymphoma (DLBCL), which is the most frequent non-Hodgkin lymphoma. In this study, we first characterized by MFC the expression of 27 lymphoid markers in 16 DLBCL-derived cell lines to establish a robust algorithm for their authentication. Then, using the expression profile in DLBCL samples of the genes encoding B lymphoid markers that are routinely investigated by MFC, we built a gene expression-based risk score, based on the expression level of BCL2, BCL6, CD11c, and LAIR1, to predict the outcome of patients with DLBCL. This risk score allowed splitting patients in four risk groups, and was an independent predictor factor of overall survival when compared with the previously published prognostic factors. Lastly, to investigate the potential correlation between BCL2, BCL6, CD11c, and LAIR1 protein level and resistance to treatment, we investigated the response of the 16 DLBCL cell lines to cyclophosphamide, etoposide, doxorubicin, and gemcitabine. We found a correlation between BCL6 overexpression and resistance to etoposide. These results show the interest of MFC for the routine characterization of DLBCL cells and tumors samples for research and diagnostic/prognostic purposes.

| S-EPMC6678649 | biostudies-literature

The critical role of RasGRP4 in the growth of diffuse large B cell lymphoma.

Project description:BackgroundThis study aimed to confirm that blocking RasGRP4 can effectively slow down the growth of DLBCL both in vitro and in vivo and ascertain the role of RasGRP4 in the prognosis of DLBCL clinically.MethodsRasGRP4 expression levels were examined in benign tissues and lymphomas. In order to verify somatic mutation in RasGRP4 gene, cDNA sequencing was performed in DLBCL patients. RasGRP4-dependent cell proliferation, mitochondrial membrane potential, oxidative stress levels and signaling pathway changes were measured by knockdown of RasGRP4. Tumor growth was monitored in xenografted lymphoma model. Clinical data were collected to confirm the role of RasGRP4 in DLBCL.ResultsRasGRP4 expression was significantly elevated in DLBCL while no somatic mutations were detected of this gene in DLBCL patients. Decreased RasGRP4 significantly inhibited cell proliferation by simultaneously reducing mitosis and promoting apoptosis and increased the oxidative stress levels. Mechanistically, reduced expression of RasGRP4 decreased ERK while increased JNK expression in SUDHL-4 cells. Knockdown of RasGRP4 also significantly inhibited tumor formation in vivo. Furthermore, RasGRP4 expression levels were significantly higher in patients with larger DLBCL lesions (P?=?0.0004), high-risk international prognostic index score groups (P?=?0.0042), and its expression was positively correlated with maximum standardized uptake value in DLBCL (P?=?0.0004).ConclusionsThese findings indicate the oncogenic role of RasGRP4 in DLBCL, suggesting it as a prognostic biomarker and potential therapeutic target in DLBCL.

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