Expression data from DLBCL tumor biopsies and TMD8 cell line
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ABSTRACT:
PROVIDER: PRJNA363005 | ENA |
REPOSITORIES: ENA
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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.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2017-04-30 | GSE93986 | GEO
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.
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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.
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Project description:Relapsed and refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell malignancy that has inadequate treatment options. BTK inhibitors such as acalabrutinib have demonstrated preclinical and clinical activity in the activated B-cell (ABC) DLBCL subset however tumour responses are modest resulting in short-term tumour control. To understand what limits BTK inhibits signaling mediated resistance was explored in vitro. BTK inhibition delivered through siRNA-mediated BTK down regulation or acalabrutinib treatment identified of AKT as a candidate resistance driver. In vitro combination of acalabrutinib with the AKT inhibitor capivasertib increased cell death in ABC-DLBCL cell lines, TMD8 and OCI-LY10. In vivo the combination benefit in resulted in tumor regressions in TMD8, OCI-LY10 tumor xenografts and stasis in an ABC-DLBCL PDX tumor which was associated with a reduction of S6 kinase phosphorylation and suppression of mTORC1 signaling gene expression. Notably RNA sequencing analysis of TMD8 cells and xenograft tumors revealed an enhancement of MS4A1 (CD20) gene expression following combination treatment in surviving cells. Adding rituximab to the combination further augmented in vivo efficacy driving to persistent tumor regressions of TMD8 tumours that were sustained following dosing cessation. In ABC-DLBCL targeting the BTK inhibitor induced feedback AKT reactivation can enhance efficacy, and furthermore, the combination of acalabrutinib and capivasertib primes tumor cells for CD20 targeted therapy with potential to deliver long-term durable responses in ABC-DLCBL.
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Project description:The mass spectrometry-based quantitative proteome analysis was firstly performed to reveal the role of up-regulated CENPF in DLBCL cell line, then various proteins were found mainly enriched with various ubiquitin related kinases activity and ubiquitination process, then the ubiquitinome analysis was further performed in this study to reveal the promising signaling pathway.
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Project description:Relapsed and refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell malignancy that has inadequate treatment options. BTK inhibitors such as acalabrutinib have demonstrated preclinical and clinical activity in the activated B-cell (ABC) DLBCL subset however tumour responses are modest resulting in short-term tumour control. To understand what limits BTK inhibits signaling mediated resistance was explored in vitro. BTK inhibition delivered through siRNA-mediated BTK down regulation or acalabrutinib treatment identified of AKT as a candidate resistance driver. In vitro combination of acalabrutinib with the AKT inhibitor capivasertib increased cell death in ABC-DLBCL cell lines, TMD8 and OCI-LY10. In vivo the combination benefit in resulted in tumor regressions in TMD8, OCI-LY10 tumor xenografts and stasis in an ABC-DLBCL PDX tumor which was associated with a reduction of S6 kinase phosphorylation and suppression of mTORC1 signaling gene expression. Notably RNA sequencing analysis of TMD8 cells and xenograft tumors revealed an enhancement of MS4A1 (CD20) gene expression following combination treatment in surviving cells. Adding rituximab to the combination further augmented in vivo efficacy driving to persistent tumor regressions of TMD8 tumours that were sustained following dosing cessation. In ABC-DLBCL targeting the BTK inhibitor induced feedback AKT reactivation can enhance efficacy, and furthermore, the combination of acalabrutinib and capivasertib primes tumor cells for CD20 targeted therapy with potential to deliver long-term durable responses in ABC-DLCBL.
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