RNA-seq analysis of paired Non-Hodgkin's lymphoma (NHL) tumor samples at pretreatment and after mosunetuzumab relapse coinciding with the loss of CD20 protein
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ABSTRACT:
PROVIDER: PRJNA1020570 | ENA |
REPOSITORIES: ENA
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Project description:CD20 protein-negative diseases were observed for a subset of patients with B-NHL that relapsed after initial responses to mosunetuzumab. For many of these tumors, whole exome (WES) and RNA-seq failed to detect any MS4A1 genetic variants or loss of CD20 mRNA, which could have explained the apparent loss of CD20 protein. For this study, we obtained formalin-fixed paraffin-embedded (FFPE) tumor samples from a similar cohort of four additional patients relapsing after mosunetuzumab, and performed RNA-seq to look for changes in the splicing pattern of CD20.
2023-12-08 | GSE243919 | GEO
Project description:Covalent Bruton's tyrosine kinase inhibitors (BTKis) have transformed the treatment of B-cell non-Hodgkin lymphoma (B-NHL), including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but their activity has been limited by off-target toxicity and acquired drug resistance. TG-1701 is a novel irreversible and highly specific BTKi being presently under study in a phase 1 clinical trial in patients with relapsed/refractory B-NHL alone and in combination with ublituximab, a CD20 antibody, and umbralisib, a dual PI3Kδ and CK1ε inhibitor. Here we show, for the first time that phosphoproteomic analysis of CLL patients receiving a BTKi (TG-1701) led to a non-supervised clustering that matched the clinical outcomes and separated a group of “responders” from a group of “non-responders”. This clustering was based on a selected list of 96 phosphosites, with Ikaros-Ser442/445 phosphorylation as a potential marker for TG-1701 efficacy. RNA-seq analysis followed by qPCR and western blot validation further revealed that TG-1701 treatment blunted the Ikaros gene signature only in responder patients, as well as in BTKi-sensitive, but not BTKi-insensitive, B-NHL cell lines and xenografts. Importantly, and in contrast with ibrutinib, TG-1701 did not impair FcγR-driven antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) triggered by the anti-CD20 antibodies rituximab and ublituximab in a multicellular MCL co-culture system. In addition, TG-1701 cooperated with ublituximab coupled to umbralisib (also referred as the U2 regimen) in reducing the tumor growth in both ibrutinib-sensitive and ibrutinib-insensitive mouse models of MCL. Altogether, these data validate phosphoproteomic as a broken thread to omics analysis in the clinic and support the use of TG-1701-U2 combination in R/R B-NHL patients, irrespective of prior response to ibrutinib.
2021-09-22 | PXD023231 | Pride
Project description:CD20 is a clinically validated target for Non-Hodgkin’s lymphomas and autoimmune diseases. Interactions of CD20 with the B cell receptor (BCR) and components of the BCR signaling cascade have been reported. In this study we show that antibodies against CD20 or activation of the BCR by specific antibodies induce very similar expression patterns of up- or down-regulated genes in NHL cell lines indicating that CD20 may play a role in BCR signaling and vice versa. We used microarray data to show that antibodies against CD20 or activation of the BCR by specific antibodies induce very similar expression patterns of up- or down-regulated genes in NHL cell lines indicating that CD20 may play a role in BCR signaling and vice versa.
2013-07-23 | GSE23394 | GEO
Project description:CD20 is a clinically validated target for Non-Hodgkin’s lymphomas and autoimmune diseases. Interactions of CD20 with the B cell receptor (BCR) and components of the BCR signaling cascade have been reported. In this study we show that antibodies against CD20 or activation of the BCR by specific antibodies induce very similar expression patterns of up- or down-regulated genes in NHL cell lines indicating that CD20 may play a role in BCR signaling and vice versa. We used microarray data to show that antibodies against CD20 or activation of the BCR by specific antibodies induce very similar expression patterns of up- or down-regulated genes in NHL cell lines indicating that CD20 may play a role in BCR signaling and vice versa. Four different cell lines were treated with various antibodies for 4h (3 replicates per treatment), all in all 96 arrays were analysed for 32 samples. Changes were calculated relative to control/reference experiments. Expression patterns of each treatment were compared to determine overlaps.
2013-07-23 | E-GEOD-23394 | biostudies-arrayexpress
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
Project description:MS-based proteomics and phosphoproteomics study based on 7 paired diagnosis-first relapse AML patient samples
2020-06-12 | PXD018359 | Pride
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.
2014-09-01 | GSE54201 | GEO
Project description:CD20 is an integrate membrane protein expressed on the surface of normal and malignant B-cells. It is an excellent molecular target for monoclonal antibodies (mAbs) that are widely used in the treatment of non-Hodgkin’s lymphomas (NHL) and chronic lymphocytic leukemia (CLL). Anti-CD20-directed therapies are the most effective, successful and widely used therapeutic monoclonal antibodies, routinely incorporated into all phases of conventional treatment, including first-line, maintenance and salvage treatment. Nonetheless, the overall response rates to treatment have been reported to be 46-67% for rituximab, and in patients relapsing after initial rituximab treatment the response rate is ~40%. A number of mechanisms have been proposed to account for this inefficiency, including modulation of surface CD20 levels, occurring due to both transcriptional and posttranscriptional regulations. Our observations strongly imply that the observed CD20 down-regulation relies on transcriptional mechanism and delineate new perspectives in the field of CD20 regulation. Since many of the new therapeutic agents selectively inhibit specific signaling pathways, combining the compounds that target different mechanisms of cell growth and survival is a particularly attractive approach. However, optimal combinations of novel treatment modalities with already existing ones should take into account potential ”off-target” activity yet to be identified that could unexpectedly result in high toxicity and/or impaired outcomes of treatment
2014-12-31 | GSE50929 | GEO
Project description:To identify the differentially expressed miRs in the plasmas of non-Hodgkin's lymphoma (NHL) patients, we screened NHL samples using microarrays.
2011-12-31 | GSE22604 | GEO
Project description:Relapse neuroblastoma were characterized by sequencing, gene expression, arrayCGH and genome-wide methylation. This data set contains the aCGH data. Array from tumours at relapse were compared to pretreatment tumours and corresponding normal samples.
2015-06-19 | E-GEOD-65304 | biostudies-arrayexpress