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Tonic B-Cell-Receptor Signaling in the Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma

ABSTRACT: Multiple types of B-cell lymphoma respond clinically to BTK inhibition, reflecting their dependence on B-cell receptor signaling. The germinal center B-cell subtype of diffuse large B-cell lymphoma resists BTK inhibition, but we found that B-cell receptor elimination in cell lines of this lymphoma type reduced their size and proliferation. Their B-cell receptor signals in a “tonic”, antigen-independent manner, requiring SYK, CD19, and phosphorylation of a specific tyrosine residue in the CD79A immunoreceptor tyrosine-based activation motif domain. The effect of B-cell receptor elimination or inhibition in these lines is proportional to their B-cell receptor surface density and its relative contribution to AKT activity, on which these lines uniformly depend, and is rescued by spontaneous or induced loss of PTEN protein. Biomarker-guided targeting of tonic B-cell receptor signaling may improve treatment of germinal center B-cell lymphoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE80615 | GEO | 2017/01/01

SECONDARY ACCESSION(S): PRJNA319490

REPOSITORIES: GEO

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Homo sapiens

Project description:Tonic B-Cell-Receptor Signaling in the Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma

| PRJNA319490 | ENA

Modeling the clinical phenotype of BTK inhibition in the mature murine immune system

Project description:Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice. We implicate BTK in tonic BCR signaling, demonstrate dependence of the T3 B cell subset and IgM surface expression on BTK activity, and find that B1 cells survive and function independently of BTK. While BTK inhibition does not impact humoral memory survival, antigen-driven clonal expansion of memory B cells and antibody secreting cell generation are inhibited. These data define the role of BTK in the mature immune system and mechanistically predict the clinical phenotype of BTK inhibition. We used Affymetrix genechips to profile the transcriptional changes downstream of BTK inhibition after in vivo B-cell activation by anti-IgD Mice were injected with the novel BTK inhibitor PF-303 2 hours prior to anti-IgD mediated in vivo B-cell activation; B-cells where harvested 2 hours after anti-IgD activation and RNA isolated.

2014-08-01 | E-GEOD-56483 | biostudies-arrayexpress

Gene expression profiling of cell lines derived from classical Hodgkin lymphoma

Project description:Hodgkin lymphoma is derived from germinal center / post-germinal center B cells. To determine differentially expressed genes between Hodgkin Reed Sternberg cells and their presumed cell of origin we investigated the expression profiles of 5 commonly used Hodgkin lymphoma cell lines as compared to reactive germinal centers.

2010-12-11 | E-GEOD-25986 | biostudies-arrayexpress

Modeling the clinical phenotype of BTK inhibition in the mature murine immune system

2014-08-01 | GSE56483 | GEO

Gene expression profiling of Hodgkin lymphoma cell lines

Project description:Hodgkin lymphoma is derived from germinal center / post-germinal center B cells. Gene expression profilies of the Hodgkin lymphoma cell lines were compared to 5 samples of CD77+ centroblasts derived from reactive tonsils

2012-08-31 | E-GEOD-39132 | biostudies-arrayexpress

Gene expression profiling of microdissected HRS cells is correlated with primary treatment outcome

Project description:Hodgkin lymphoma is derived from germinal center / post-germinal center B cells.

2012-08-31 | GSE39134 | GEO

Gene expression profiling of microdissected HRS cells

Project description:Hodgkin lymphoma is derived from germinal center / post-germinal center B cells.

2012-08-31 | GSE39133 | GEO

Gene expression profiling of cell lines derived from classical Hodgkin lymphoma

Project description:Hodgkin lymphoma is derived from germinal center / post-germinal center B cells.

2010-12-11 | GSE25986 | GEO

Gene expression profiling of Hodgkin lymphoma cell lines

Project description:Hodgkin lymphoma is derived from germinal center / post-germinal center B cells.

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RNA sequencing reveals that withaferin A reduces overexpression of Bruton's tyrosine kinase in glucocorticoid resistant multiple myeloma cells

Project description:Multiple myeloma (MM) is an incurable hematological malignancy characterized by the uncontrolled growth of plasma cells in the bone marrow. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to multiple existing anti-cancer drugs. Often, this therapy resistance is associated with constitutive activation of Bruton tyrosine kinase (BTK) dependent B-cell receptor (BCR) signaling. Novel kinase inhibitors covalently targeting BCR signaling, including the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical Withaferin A (WA), have therefore gained pharmaceutical interest. Remarkably, glucocorticoid (GC)-resistant MM cells overexpressing BTK are more sensitive to WA then to IBR. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. Our results demonstrate that WA treatment triggers dual inhibition of BCR signaling by transcriptional downregulation and covalent cysteine-dependent kinase inhibition of BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal imaging microscopy. Altogether, we show that covalent BCR-BTK kinase inhibition by WA represents an attractive strategy to treat GC-resistant MM.

2021-03-31 | GSE162475 | GEO

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