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Monoclonal antibodies binding to different epitopes of CD20 differentially sensitizes DLBCL to different classes of chemotherapy

ABSTRACT: To investigate the differential gene expression profiles induced by rituximab and ofatumumab, we treated DLBCL cell lines U2932 and TMD8 with these monoclonal antibodies and analyzed their gene expression profiles

ORGANISM(S): Homo sapiens

PROVIDER: GSE228687 | GEO | 2023/04/07

REPOSITORIES: GEO

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The ETS inhibitors YK-4-279 and TK-216 have anti-tumor activity in lymphomas and interfere with SPIB in activated B cell-like type diffuse large B cell lymphoma

Project description:TMD8 and U2932 were treated with YK-4-279 for 4 and 8 hours.

2021-05-01 | GSE114022 | GEO

Differential regulation patterns of anti-CD20 mAbs in MCL

Project description:We investigated the differential regulation patterns of type I anti-CD20 monoclonal antibody (mAb) rituximab and type II obinutuzumab on a transcriptional level. Using a panel of MCL cell lines, we determined the effects of obinutuzumab and rituximab as monotherapies as well as in combination on cell viability and proliferation. Obinutuzumab induced a higher reduction in cell proliferation in each mantle cell lymphoma cell line than rituximab did. Results indicate a common pattern of expression changes after binding of anti-CD20 mAbs, but also reveal a significant difference between type I and type II treatment. Combination treatment resulted in a rituximab-like expression pattern. Many deregulated genes were associated with stress signalling, cell death, immune response and other functional clusters. Our analyses identified different and antibody-specific downstream expression patterns of obinutuzumab and rituximab, which may represent the molecular basis of the superior effect of obinutuzumab in comparison to rituximab.

2014-12-31 | GSE54169 | GEO

(1) Effect of KLHL6 loss on the transcriptome in DLBCL upon NOTCH ligand stimulation. (2) Effect of KLHL6 and NOTCH2 loss on the transcriptome in DLBCL. (3) Effect of DLBCL-associated NOTCH2 mutants on the transcriptome in DLBCL.

Project description:(1) Assessment of the transcriptional changes regulated by KLHL6 upon NOTCH ligand stimulation. Bulk RNA-seq in KLHL6 WT or KO U2932 cells was performed upon incubation with stromal OP9 cells stably expressing NOTCH ligand DLL1. (2) Assessment of the transcriptional changes regulated by the KLHL6-NOTCH2 axis in a xenotransplant model of DLBCL. Bulk RNA-seq was performed in in KLHL6+/+NOTCH2+/+(WT), KLHL6-/-NOTCH2+/+(K6-KO), KLHL6+/+NOTCH2-/-(N2-KO), KLHL6-/-NOTCH2-/-(DKO) U2932 cells xenotranplanted in NSG mice trated with CHOP. (3) Assessment of the transcriptional changes regulated by the DLBCL-associated NOTCH2 mutants. Bulk RNA-seq was performed inU2932 cells stably expressing NOTCH2(WT), NOTCH2(S2156A), NOTCH2(R2400*) or NOTCH2(Q2140*).

2024-05-03 | GSE231624 | GEO

Small molecule inhibitor of BCL2 in combination with RCHOP is effective in CD20 negative lymphoma

Project description:Rituximab alone or in combination with chemotherapeutics is the first-line therapy for variety of lymphoproliferative disorders including low- and high grade non-Hodgkin’s lymphomas (NHL). Although the complete response rate is quite impressive, vast majority of patient presents recurrent disease. The association between CD20 expression and clinical outcome in patients strongly suggests that reduced CD20 expression leads to inferior response to RCHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In order to understand how loss of CD20 leads to development of RCHOP resistance, we developed rituximab resistant DOHH2 model in vivo by chronic exposure to rituximab. Characterization of several resistant in vivo xenografts revealed one model that maintained resistance to an acute dose of rituximab and demonstrated loss of CD20. Further characterization of the model demonstrated a loss of CD20 is associated with over expression of BCL2 and BIM. In vivo efficacy studies showed resistant line is insensitive to acute dose of RCHOP and treatment with an inhibitor of BCL2 (ABT199) in combination with chemotherapy resulted in better efficacy than RCHOP alone. We have identified an in vivo model of DLBCL where loss of CD20 and over expression of anti-apoptotic protein BCL2 leads to RCHOP resistance. These data suggest the addition of BCL2 inhibitor to chemotherapy might be effective in treating CD20 negative lymphomas. mRNA profiles of parental and rituximab resistant DOHH2 xenograft were generated by deep sequencing using Illumina HiSeq

2014-09-01 | E-GEOD-54201 | biostudies-arrayexpress

Small molecule inhibitor of BCL2 in combination with RCHOP is effective in CD20 negative lymphoma

2014-09-01 | GSE54201 | GEO

RNA-Seq for a differential gene expression bewteen KLHL14 wild-type(+/+) and KLHL14 knockout(-/-) TMD8 ABC-DLBCL cell line upon treatment with a BTK inhibitor, ibrutinib

Project description:The goal of this study is to examine gene expression changes in TMD8 KLHL14(+/+) or TMD8 KLHL14(-/-) cells during ibrutinib treatment. The samples have 35 to 63 million pass filter reads with more than 92% of bases above the quality score of Q30.The average mapping rate of all samples is 95%. Unique alignment is above 86%. There are 3.65 to 6.25% unmapped reads.The mapping statistics are calculated using Picard software. The samples have between 0.86-1.29% ribosomal bases. Percent coding bases are between 58-62%. Percent UTR bases are 27-31%, and mRNA bases are between 87-90% for all the samples. We show that TMD8 KLHL14(-/-) cells have less down-regulation of NF-kB signatures and IL10/JAK1/STAT3 signatures upon ibrutinib treatment when compared to TMD8 KLHL14(+/+) cells.

2020-03-03 | GSE141143 | GEO

Expression data from DLBCL tumor biopsies

Project description:Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton’s tyrosine kinase (BTK)–mediated B-cell receptor (BCR) signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance. Ibrutinib-resistant TMD8 cells had higher BCL2 gene expression and increased sensitivity to ABT-199, a BCL-2 inhibitor. Consistently, clinical samples from ABC-DLBCL patients who experienced poorer response to ibrutinib had higher BCL2 gene expression. We further demonstrated synergistic growth suppression by ibrutinib and ABT-199 in multiple ABC-DLBCL, GCB-DLBCL, and FL lymphoma cell lines. The combination of both drugs also reduced colony formation, increased apoptosis, and inhibited tumor growth in a TMD8 xenograft model. A synergistic combination effect was also found in ibrutinib-resistant cells generated by either genetic mutation or drug treatment. Together, these findings suggest a potential clinical benefit from ibrutinib and ABT-199 combination therapy.

2017-04-30 | GSE93984 | GEO