scholarly journals Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Markus Schick ◽  
Le Zhang ◽  
Sabine Maurer ◽  
Hans Carlo Maurer ◽  
Konstandina Isaakaidis ◽  
...  
Keyword(s):  
Dna Repair ◽  
B Cell ◽  
Cell Lymphoma ◽  
Synthetic Lethality ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Parp Inhibition ◽  
Post Translational Modification ◽  
Genome Maintenance ◽  
A Genome

AbstractSUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we here identify the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to Poly-ADP-Ribose-Polymerase (PARP) inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma.

scholarly journals Essentiality of CREBBP in EP300 truncated B-cell lymphoma revealed by genome-wide CRISPR-Cas9 screen

2019 ◽  
Author(s):  
Man Nie ◽  
Likun Du ◽  
Bo Zhang ◽  
Weicheng Ren ◽  
Julia Joung ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Time Course ◽  
Course Design ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Genome Wide ◽  
A Genome

AbstractHistone acetyltransferases (HATs), including CREBBP and EP300, are frequently mutated in B-cell malignancies and usually play a tumor-suppressive role. In this study, we performed whole genome and transcriptome sequencing and a genome-wide CRISPR-Cas9 knockout screen to study a germinal center B-cell like diffuse large B-cell lymphoma (DLBCL) cell line (RC-K8). Using a summarizing method that is optimized to address the complexity introduced by the time-course design, we identified a distinct pattern of genetic essentialities in RC-K8, including a dependency on CREBBP and MDM2, shown already at early time points and a gradually increased dependency on oxidative phosphorylation related genes. The dependency on CREBBP is associated with the corresponding genetic alterations identified in this cell line, i.e. a balanced translocation involves EP300, which resulted in a truncated form of protein that lacks the critical bromodomain and HAT domain. We further evaluated the previously published CRISPR-Cas9 screens and identified a genetic essentiality of CREBBP or EP300 gene in a small set of cancer cell lines, including several DLBCL cell lines that are highly sensitive for EP300 knockout and with CREBBP mutations or copy number loss. The dependency of the remaining HAT function in CREBBP and/or EP300-deficient genotype was validated by testing the HAT-domain inhibitor A-485. Our study suggests that integration of the unbiased, time-course-based functional screen results with the genomic and transcriptomic data can identify druggable vulnerability in individual or subgroups of cell lines/patients, which may help to develop more effective therapeutic strategies for cancers that are genetically highly heterogeneous, like DLBCL.

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

2021 ◽  
Vol 38 (4) ◽  
Author(s):  
Jiazheng Li ◽  
Yan Huang ◽  
Yun Zhang ◽  
Jingjing Wen ◽  
Yanxin Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Venn Diagram ◽  
Potential Candidate ◽  
Large B Cell Lymphoma ◽  
Ibrutinib Resistance ◽  
Large B Cell ◽  
Geo Database

AbstractIbrutinib has clear efficacy for activated B-cell-like diffuse large B cell lymphoma (ABC-DLBCL) in previous clinical researches. However, the resistance of Ibrutinib has limited its therapeutic benefit and the potential mechanism remains unclear. This study was aimed to identify potential candidate genes and miRNA targets to overcome Ibrutinib resistance in ABC-DLBCL. First, two expression profiles were downloaded from the GEO database, which used to identify the DEGs related to Ibrutinib resistance in ABC-DLBCL cell lines by GEO2R analysis separately. And the common DEGs were obtained though Venn diagram. Then Gene ontology (GO) and pathway enrichment analysis were conducted by DAVID database. From STRING database, BCL6, IL10, IL2RB, IRF4, CD80, PRDM1and GZMB were determined to be the hub genes by protein–protein interaction (PPI) network. Through miRNA-mRNA targeting network, we found that BCL6, IRF4, CD80, and PRDM1 were common target genes of miR-30 family. The cBioPortal database showed that BCL6 had the highest level of genetic alterations among DLBCL. In addition, another expression profile from GEO database showed that BCL6 was significantly high expression in no responsive patients after Ibrutinib treatment, and the receiver operating characteristic (ROC) curve which was used to evaluate the relationship between BCL6 expression and its effect was 0.67. MTT assay showed that treatment with FX1 (a BCL6 inhibitor) can enhance the sensitivity of Ibrutinib in C481S BTK HBL-1 cells. The results suggested that BCL6 and miR-30 family maybe associate with Ibrutinib resistance in ABC-DLBCL.

Anaplastic Variant of Diffuse Large B-cell Lymphoma Displays Intricate Genetic Alterations and Distinct Biological Features

2017 ◽  
Vol 41 (10) ◽  
pp. 1322-1332 ◽  
Author(s):  
Mingyang Li ◽  
Yixiong Liu ◽  
Yingmei Wang ◽  
Gang Chen ◽  
Qiongrong Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Biological Features ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Targeting B-cell receptor and PI3K signaling in diffuse large B-cell lymphoma

Blood ◽  
2021 ◽  
Author(s):  
Wendan Xu ◽  
Philipp Berning ◽  
Georg Lenz
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Genetic Alterations ◽  
B Cell Receptor ◽  
Special Focus ◽  
Large B Cell Lymphoma ◽  
Bcr Signaling ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous diagnostic category comprising distinct molecular subtypes characterized by diverse genetic aberrations that dictate patient outcome. As roughly one-third of DLBCL patients are not cured by current standard chemo-immunotherapy a better understanding of the molecular pathogenesis is warranted to improve outcome. B-cell receptor (BCR) signaling is crucial for the development, growth and survival of both normal and a substantial fraction of malignant B-cells. Various analyses revealed genetic alterations of central components of the BCR or its downstream signaling effectors in some subtypes of DLBCL. Thus, BCR signaling and the downstream NF-κB and PI3K cascades have been proposed as potential targets for the treatment of DLBCL patients. As one of the main effectors of BCR activation, PI3K mediated signals play a crucial role in the pathogenesis and survival of DLBCL. In this review, we summarize our current understanding of BCR signaling with a special focus on the PI3K pathway in DLBCL and how to utilize this knowledge therapeutically.

scholarly journals Genetics of diffuse large B-cell lymphoma

Blood ◽  
2018 ◽  
Vol 131 (21) ◽  
pp. 2307-2319 ◽  
Author(s):  
Laura Pasqualucci ◽  
Riccardo Dalla-Favera
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Current Knowledge ◽  
Immune Surveillance ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Transformation Process ◽  
Large B Cell Lymphoma ◽  
Epigenetic Remodeling ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL), the most frequent subtype of lymphoid malignancy, remains a significant clinical challenge, as ∼30% of patients are not cured. Over the past decade, remarkable progress has been made in the understanding of the pathogenesis of this disease, spurred by the implementation of powerful genomic technologies that enabled the definition of its genetic and epigenetic landscape. These studies have uncovered a multitude of genomic alterations that contribute to the initiation and maintenance of the tumor clone by disrupting biological functions known to be critical for the normal biology of its cells of origin, germinal center B cells. The identified alterations involve epigenetic remodeling, block of differentiation, escape from immune surveillance, and the constitutive activation of several signal transduction pathways. This wealth of new information offers unique opportunities for the development of improved diagnostic and prognostic tools that could help guide the clinical management of DLBCL patients. Furthermore, a number of the mutated genes identified are potentially actionable targets that are currently being explored for the development of novel therapeutic strategies. This review summarizes current knowledge of the most common genetic alterations associated with DLBCL in relation to their functional impact on the malignant transformation process, and discusses their clinical implications for mechanism-based therapeutics.

scholarly journals Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report

Blood ◽  
2020 ◽  
Vol 135 (20) ◽  
pp. 1759-1771 ◽  
Author(s):  
Stuart E. Lacy ◽  
Sharon L. Barrans ◽  
Philip A. Beer ◽  
Daniel Painter ◽  
Alexandra G. Smith ◽  
...  
Keyword(s):  
B Cell ◽  
Poor Prognosis ◽  
Molecular Subtypes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Classification Systems ◽  
Targeted Sequencing ◽  
Research Network ◽  
The Impact

Abstract Based on the profile of genetic alterations occurring in tumor samples from selected diffuse large B-cell lymphoma (DLBCL) patients, 2 recent whole-exome sequencing studies proposed partially overlapping classification systems. Using clustering techniques applied to targeted sequencing data derived from a large unselected population-based patient cohort with full clinical follow-up (n = 928), we investigated whether molecular subtypes can be robustly identified using methods potentially applicable in routine clinical practice. DNA extracted from DLBCL tumors diagnosed in patients residing in a catchment population of ∼4 million (14 centers) were sequenced with a targeted 293-gene hematological-malignancy panel. Bernoulli mixture-model clustering was applied and the resulting subtypes analyzed in relation to their clinical characteristics and outcomes. Five molecular subtypes were resolved, termed MYD88, BCL2, SOCS1/SGK1, TET2/SGK1, and NOTCH2, along with an unclassified group. The subtypes characterized by genetic alterations of BCL2, NOTCH2, and MYD88 recapitulated recent studies showing good, intermediate, and poor prognosis, respectively. The SOCS1/SGK1 subtype showed biological overlap with primary mediastinal B-cell lymphoma and conferred excellent prognosis. Although not identified as a distinct cluster, NOTCH1 mutation was associated with poor prognosis. The impact of TP53 mutation varied with genomic subtypes, conferring no effect in the NOTCH2 subtype and poor prognosis in the MYD88 subtype. Our findings confirm the existence of molecular subtypes of DLBCL, providing evidence that genomic tests have prognostic significance in non-selected DLBCL patients. The identification of both good and poor risk subtypes in patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) clearly show the clinical value of the approach, confirming the need for a consensus classification.

scholarly journals The Spectrum of MYC Alterations in Diffuse Large B-Cell Lymphoma

2020 ◽  
Vol 143 (6) ◽  
pp. 520-528
Author(s):  
Yang Xia ◽  
Xinlian Zhang
Keyword(s):  
B Cell ◽  
Clinical Outcomes ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Gene Copy ◽  
Novel Therapy ◽  
Large B Cell Lymphoma ◽  
Large B Cell

MYC, as a powerful transcription factor, plays a vital role in various cancers. The clinical significance of MYC alterations in diffuse large B-cell lymphoma (DLBCL) has been investigated for a long time. In this study, we comprehensively summarize the different alterations of MYC in DLBCL, including MYC overexpression, <i>MYC</i> translocations, <i>MYC</i> mutations, and increased gene copy number of <i>MYC</i>. Noteworthy, lone MYC overexpression or <i>MYC</i> translocation is not significantly associated with poor clinical outcomes, and their detrimental effects depend on the genetic alterations of BCL2 or BCL6. Both double-expressor DLBCL (DE-DLBCL), defined as overexpression of MYC and BCL2 proteins, and double-hit lymphoma (DHL), defined as a dual translocation of <i>MYC</i> together with <i>BCL2</i> or <i>BCL6</i>, represent the distinct subgroups of DLBCL with inferior clinical outcomes. The mechanism may be that MYC activation induces cell proliferation, without the threat of the apoptotic brake in the presence of BCL2 overexpression. In addition, most of <i>MYC</i> mutations are present with favorable prognosis, and the nonsignificant effect of MYC copy number amplification has been observed. It has been proved that cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab show limited effects for DHL or DE-DLBCL, and the rituximab plus dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin seem to be efficacious for DHL. The novel therapy is urgently needed for clinical improvement in DHL and DE-DLBCL.

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