scholarly journals Combination Treatment with GSK126 and Pomalidomide Induces B-Cell Differentiation in EZH2 Gain-of-Function Mutant Diffuse Large B-Cell Lymphoma

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2541
Author(s):  
Sungryul Park ◽  
Seung-Hyun Jo ◽  
Jong-Hwan Kim ◽  
Seon-Young Kim ◽  
Jae Du Ha ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Zinc Finger ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Differentiation ◽  
Gain Of Function ◽  
Polycomb Repressive Complex 2 ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates genes involved in cell lineage and differentiation through methylating lysine 27 on histone H3 (H3K27me3). Recurrent gain-of-function mutations of EZH2 have been identified in various cancer types, in particular, diffuse large B-cell lymphoma (DLBCL), through large-scale genome-wide association studies and EZH2 depletion or pharmacological inhibition has been shown to exert an antiproliferative effect on cancer cells, both in vitro and in vivo. In the current study, a combination of pomalidomide and GSK126 synergistically inhibited the growth of EZH2 gain-of-function mutant Diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, this synergistic effect appeared to be dependent on cereblon (CRBN), a cellular receptor of pomalidomide, but not degradation of IKAROS family zinc finger 1 (IKZF1) or IKAROS family zinc finger 3 (IKZF3). RNA sequencing analyses revealed that co-treatment with GSK126 and pomalidomide induced specific gene sets involved in B-cell differentiation and apoptosis. Synergistic growth inhibition and B-cell differentiation were further validated in xenograft mouse models. Our collective results provide a molecular basis for the mechanisms underlying the combined therapeutic effects of PRC2 inhibitors and pomalidomide on EZH2-mutated DLBCL.

Aberrant Co-Expression of Key Transcription Factors BCL6, IRF4 and FOXP1 Are Frequently Observed in Diffuse Large B-Cell Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3761-3761
Author(s):  
Maayke Boll ◽  
Sharon L Barrans ◽  
Charles S McManamy ◽  
Andrew S Jack
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Germinal Centre ◽  
B Cell Differentiation ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse Large B-cell Lymphoma (DLBCL) is classified into germinal centre (GCB) and activated B-cell (ABC) type by comparison with the phenotype of normal B-cells. Using single-color immunocytochemistry, tumors can be classified using a simple algorithm based on the expression of CD10, BCL6 and IRF4. This classification may have prognostic relevance and correlates with balanced translocations involving the immunoglobulin locus. However, the phenotypic differences between normal and neoplastic cells may be of greater relevance to understanding the pathogenesis of DLBCL and in developing effective diagnostic techniques. To investigate this we examined the co-expression of BCL6, IRF4 and FOXP1. These are key transcription factors that regulate the process of germinal centre and post germinal centre B-cell differentiation. Abnormal co-expression of these molecules would be expected to have major effects on the overall cellular phenotype. A multi-color immunofluorescence (MCIF) technique was developed that allowed the co-expression of these markers to be assessed in relation to the PAX5 positive B-cell population. The use of a multi-color technique allows the distinction between co-expression at the level of individual cells and differentiation within the tumor as a whole. We first determined the pattern of expression of these transcription factors in normal B-cells. In reactive lymph nodes the expression of BCL6, IRF4 and FOXP1 was almost mutually exclusive with only a small proportion of co-expressing cells. In a series of 61 DLBCL co-expression of both BCL6/IRF4 and IRF4/FOXP1 was found in 41/61 (67%) of the cases. In most of these cases the level of co-expression was greater than 50% of the PAX5 positive large lymphoid cells. Co-expression was not present in 11/61 (18%) of the tumors. In the remaining cases there was co-expression of either BCL6/IRF4 or IRF4/FOXP1. There was no correlation between the occurrence of co-expression of these combinations of transcription factors and the expression of CD10 or the classification into GCB and ABC phenotypes. In 16 of the cases the sample used was a small needle core biopsy in which assessment of nodal architecture was impossible. In these cases it was possible to confidently determine the presence of abnormal co-expression in 14/16 (87.5%) of the cases. One explanation for the aberrant co-expression of BCL6 and IRF4 in DLBCL would be the presence of a 3q27 rearrangement leading to dysregulation of BCL6 expression. However, in this series there was no correlation between BCL6/IRF4 co-expression and abnormalities of 3q27 detected by interphase FISH. These results show that in the majority of cases of DLBCL the key transcription factors regulating post germinal centre B-cell differentiation are expressed in combinations not seen in normal B-cells. This is likely to be a central element in the pathogenesis of these tumors. The ability to reliably identify these abnormalities by MCIF has potential value in improving the reliability of diagnosis of DLBCL when only small biopsy samples are available and it is likely that this approach can be extended to other types of lymphoma.

scholarly journals Role of ETS1 in the Transcriptional Network of Diffuse Large B Cell Lymphoma of the Activated B Cell-Like Type

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1912
Author(s):  
Valdemar Priebe ◽  
Giulio Sartori ◽  
Sara Napoli ◽  
Elaine Yee Lin Chung ◽  
Luciano Cascione ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Differentiation ◽  
Sequencing Data ◽  
B Cell Signaling ◽  
Large B Cell Lymphoma ◽  
Novel Target ◽  
Signaling Activation ◽  
Large B Cell

Diffuse large B cell lymphoma (DLBCL) is a heterogenous disease that has been distinguished into at least two major molecular entities, the germinal center-like B cell (GCB) DLBCL and activated-like B cell (ABC) DLBCL, based on transcriptome expression profiling. A recurrent ch11q24.3 gain is observed in roughly a fourth of DLBCL cases resulting in the overexpression of two ETS transcription factor family members, ETS1 and FLI1. Here, we knocked down ETS1 expression by siRNA and analyzed expression changes integrating them with ChIP-seq data to identify genes directly regulated by ETS1. ETS1 silencing affected expression of genes involved in B cell signaling activation, B cell differentiation, cell cycle, and immune processes. Integration of RNA-Seq (RNA sequencing) data and ChIP-Seq (chromatin immunoprecipitation sequencing) identified 97 genes as bona fide, positively regulated direct targets of ETS1 in ABC-DLBCL. Among these was the Fc receptor for IgM, FCMR (also known as FAIM3 or Toso), which showed higher expression in ABC- than GCB-DLBCL clinical specimens. These findings show that ETS1 is contributing to the lymphomagenesis in a subset of DLBCL and identifies FCMR as a novel target of ETS1, predominantly expressed in ABC-DLBCL.

scholarly journals Knockdown of zinc finger protein 267 suppresses diffuse large B-cell lymphoma progression, metastasis, and cancer stem cell properties

Bioengineered ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 1686-1701
Author(s):  
Hua Yang ◽  
Linmei Wang ◽  
Yingbin Zheng ◽  
Guiming Hu ◽  
Hongyan Ma ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
B Cell ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Finger Protein ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals HDAC1,2 inhibition impairs EZH2- and BBAP- mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma

Oncotarget ◽  
2014 ◽  
Vol 6 (7) ◽  
pp. 4863-4887 ◽  
Author(s):  
Danielle P. Johnson ◽  
Gabriella S. Spitz ◽  
Shweta Tharkar ◽  
Steven N. Quayle ◽  
Jeffrey R. Shearstone ◽  
...  
Keyword(s):  
Dna Repair ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gain Of Function ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma

2009 ◽  
Vol 100 (5) ◽  
pp. 920-926 ◽  
Author(s):  
Suk-young Lee ◽  
Keiki Kumano ◽  
Kumi Nakazaki ◽  
Masashi Sanada ◽  
Akihiko Matsumoto ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gain Of Function ◽  
Large B Cell Lymphoma ◽  
Large B Cell
Sign in / Sign up

Export Citation Format

Share Document