THE B CELL RECEPTOR SIGNALING OUTPUT IN BURKITT?S LYMPHOMA IS GENOTYPE-SPECIFIC AND IMPACTS SENSITIVITY TOWARDS BCR SIGNALING INHIBITORS
(Abstract release date: 05/21/15)
EHA Library. Oellerich T. 06/13/15; 103128; S481
Disclosure(s): Goethe University FrankfurtHematology/Oncology
Thomas Oellerich
Contributions
Contributions
Abstract
Abstract: S481
Type: Oral Presentation + travel grant
Presentation during EHA20: From 13.06.2015 15:45 to 13.06.2015 16:00
Location: Room A7
Background
B cell antigen receptors (BCR) control important cell fate decisions of the B-lineage such as differentiation, proliferation and B cell survival. Recently, it was demonstrated that major subgroups of Burkitt lymphomas (BL) critically depend on BCR expression. The current treatment regimens consist of intensive chemotherapy in combination with anti-CD20 antibodies and show significant toxicity. Pharmacological interference with critical BCR signaling pathways might open up the possibility for targeted therapies in BL that are needed in particular for elderly patients and patients with endemic BL in developing countries.
Aims
Our study aims (i) to identify drug targets in BL, (ii) to validate selected drug targets in vitro and in vivo and (iii) to elucidate BCR induced processes.
Methods
We performed mass-spectrometry-based phosphoproteomics, transcriptome sequencing and bioinformatic analyses to elucidate BCR signaling networks in BL cell lines and patient-derived BL cells. Moreover, we validated identified drug targets using a compound library and BL xenograft models. Detailed functional analyses were performed for identifying the role of HSP90 in BL.
Results
We identified and quantified about 10.000 phospho-sites in various BL cell-lines and patient-derived BL cells, of which more than 1000 phospho-sites in almost 600 proteins were regulated in a BCR-dependent manner leading to dynamic transcription of more than 100 genes. The identified BCR signaling effectors belong to various functional groups, of which kinases, transcription factors and cytoskeleton regulators are most represented and bioinformatic analyses revealed that 83% of the identified BCR effectors were not described in the context of B cells or lymphoma before. Our data-sets allowed to investigate the dynamic interplay between receptor-triggered kinase activation, phosphorylation events and mRNA-/protein expression changes. While BCR-proximal signaling networks were concordantly regulated among genetically distinct BL cell-types, BCR-distal signaling turned out to be genotype-specific. Based on the detailed signaling information we established genotype-specific kinase/substrate/transcriptome networks that provide functional insights and information about druggable BCR-signaling pathways in BL. Predicted drug targets were furthermore validated in more than twenty BL cell lines using a compound screen that allowed us to correlate BCR signaling profiles with responsiveness to compounds targeting BCR signaling. For instance, heat shock protein 90 (HSP90) inhibition by small molecule inhibitors such as AT13387 induced apoptosis in most analyzed BL cell models and BL xenografts. This was achieved by disruption of BCR signal initiation due to destabilzation of spleen tyrosine kinase expression that turned out to critically depend on HSP90 function in BL. In contrast, compounds like Bruton’s tyrosine kinase and protein kinase B inhibitors targeting the more heterogenous BCR-distal signaling networks induced apoptosis only in certain BL cell-types.
Summary
Keyword(s): B cell lymphoma, Signal transduction, Targeted therapy
Session topic: Optimization and innovation in treating aggressive lymphomas
Type: Oral Presentation + travel grant
Presentation during EHA20: From 13.06.2015 15:45 to 13.06.2015 16:00
Location: Room A7
Background
B cell antigen receptors (BCR) control important cell fate decisions of the B-lineage such as differentiation, proliferation and B cell survival. Recently, it was demonstrated that major subgroups of Burkitt lymphomas (BL) critically depend on BCR expression. The current treatment regimens consist of intensive chemotherapy in combination with anti-CD20 antibodies and show significant toxicity. Pharmacological interference with critical BCR signaling pathways might open up the possibility for targeted therapies in BL that are needed in particular for elderly patients and patients with endemic BL in developing countries.
Aims
Our study aims (i) to identify drug targets in BL, (ii) to validate selected drug targets in vitro and in vivo and (iii) to elucidate BCR induced processes.
Methods
We performed mass-spectrometry-based phosphoproteomics, transcriptome sequencing and bioinformatic analyses to elucidate BCR signaling networks in BL cell lines and patient-derived BL cells. Moreover, we validated identified drug targets using a compound library and BL xenograft models. Detailed functional analyses were performed for identifying the role of HSP90 in BL.
Results
We identified and quantified about 10.000 phospho-sites in various BL cell-lines and patient-derived BL cells, of which more than 1000 phospho-sites in almost 600 proteins were regulated in a BCR-dependent manner leading to dynamic transcription of more than 100 genes. The identified BCR signaling effectors belong to various functional groups, of which kinases, transcription factors and cytoskeleton regulators are most represented and bioinformatic analyses revealed that 83% of the identified BCR effectors were not described in the context of B cells or lymphoma before. Our data-sets allowed to investigate the dynamic interplay between receptor-triggered kinase activation, phosphorylation events and mRNA-/protein expression changes. While BCR-proximal signaling networks were concordantly regulated among genetically distinct BL cell-types, BCR-distal signaling turned out to be genotype-specific. Based on the detailed signaling information we established genotype-specific kinase/substrate/transcriptome networks that provide functional insights and information about druggable BCR-signaling pathways in BL. Predicted drug targets were furthermore validated in more than twenty BL cell lines using a compound screen that allowed us to correlate BCR signaling profiles with responsiveness to compounds targeting BCR signaling. For instance, heat shock protein 90 (HSP90) inhibition by small molecule inhibitors such as AT13387 induced apoptosis in most analyzed BL cell models and BL xenografts. This was achieved by disruption of BCR signal initiation due to destabilzation of spleen tyrosine kinase expression that turned out to critically depend on HSP90 function in BL. In contrast, compounds like Bruton’s tyrosine kinase and protein kinase B inhibitors targeting the more heterogenous BCR-distal signaling networks induced apoptosis only in certain BL cell-types.
Summary
Taken together our study is a considerable complement to recent genetic studies that elucidated the mutational landscape in BL as it reveals mechanisms of signaling addiction to non-mutated druggable BCR effector proteins. Their further (pre)clinical evaluation as drug targets seems warranted.
Keyword(s): B cell lymphoma, Signal transduction, Targeted therapy
Session topic: Optimization and innovation in treating aggressive lymphomas
Abstract: S481
Type: Oral Presentation + travel grant
Presentation during EHA20: From 13.06.2015 15:45 to 13.06.2015 16:00
Location: Room A7
Background
B cell antigen receptors (BCR) control important cell fate decisions of the B-lineage such as differentiation, proliferation and B cell survival. Recently, it was demonstrated that major subgroups of Burkitt lymphomas (BL) critically depend on BCR expression. The current treatment regimens consist of intensive chemotherapy in combination with anti-CD20 antibodies and show significant toxicity. Pharmacological interference with critical BCR signaling pathways might open up the possibility for targeted therapies in BL that are needed in particular for elderly patients and patients with endemic BL in developing countries.
Aims
Our study aims (i) to identify drug targets in BL, (ii) to validate selected drug targets in vitro and in vivo and (iii) to elucidate BCR induced processes.
Methods
We performed mass-spectrometry-based phosphoproteomics, transcriptome sequencing and bioinformatic analyses to elucidate BCR signaling networks in BL cell lines and patient-derived BL cells. Moreover, we validated identified drug targets using a compound library and BL xenograft models. Detailed functional analyses were performed for identifying the role of HSP90 in BL.
Results
We identified and quantified about 10.000 phospho-sites in various BL cell-lines and patient-derived BL cells, of which more than 1000 phospho-sites in almost 600 proteins were regulated in a BCR-dependent manner leading to dynamic transcription of more than 100 genes. The identified BCR signaling effectors belong to various functional groups, of which kinases, transcription factors and cytoskeleton regulators are most represented and bioinformatic analyses revealed that 83% of the identified BCR effectors were not described in the context of B cells or lymphoma before. Our data-sets allowed to investigate the dynamic interplay between receptor-triggered kinase activation, phosphorylation events and mRNA-/protein expression changes. While BCR-proximal signaling networks were concordantly regulated among genetically distinct BL cell-types, BCR-distal signaling turned out to be genotype-specific. Based on the detailed signaling information we established genotype-specific kinase/substrate/transcriptome networks that provide functional insights and information about druggable BCR-signaling pathways in BL. Predicted drug targets were furthermore validated in more than twenty BL cell lines using a compound screen that allowed us to correlate BCR signaling profiles with responsiveness to compounds targeting BCR signaling. For instance, heat shock protein 90 (HSP90) inhibition by small molecule inhibitors such as AT13387 induced apoptosis in most analyzed BL cell models and BL xenografts. This was achieved by disruption of BCR signal initiation due to destabilzation of spleen tyrosine kinase expression that turned out to critically depend on HSP90 function in BL. In contrast, compounds like Bruton’s tyrosine kinase and protein kinase B inhibitors targeting the more heterogenous BCR-distal signaling networks induced apoptosis only in certain BL cell-types.
Summary
Keyword(s): B cell lymphoma, Signal transduction, Targeted therapy
Session topic: Optimization and innovation in treating aggressive lymphomas
Type: Oral Presentation + travel grant
Presentation during EHA20: From 13.06.2015 15:45 to 13.06.2015 16:00
Location: Room A7
Background
B cell antigen receptors (BCR) control important cell fate decisions of the B-lineage such as differentiation, proliferation and B cell survival. Recently, it was demonstrated that major subgroups of Burkitt lymphomas (BL) critically depend on BCR expression. The current treatment regimens consist of intensive chemotherapy in combination with anti-CD20 antibodies and show significant toxicity. Pharmacological interference with critical BCR signaling pathways might open up the possibility for targeted therapies in BL that are needed in particular for elderly patients and patients with endemic BL in developing countries.
Aims
Our study aims (i) to identify drug targets in BL, (ii) to validate selected drug targets in vitro and in vivo and (iii) to elucidate BCR induced processes.
Methods
We performed mass-spectrometry-based phosphoproteomics, transcriptome sequencing and bioinformatic analyses to elucidate BCR signaling networks in BL cell lines and patient-derived BL cells. Moreover, we validated identified drug targets using a compound library and BL xenograft models. Detailed functional analyses were performed for identifying the role of HSP90 in BL.
Results
We identified and quantified about 10.000 phospho-sites in various BL cell-lines and patient-derived BL cells, of which more than 1000 phospho-sites in almost 600 proteins were regulated in a BCR-dependent manner leading to dynamic transcription of more than 100 genes. The identified BCR signaling effectors belong to various functional groups, of which kinases, transcription factors and cytoskeleton regulators are most represented and bioinformatic analyses revealed that 83% of the identified BCR effectors were not described in the context of B cells or lymphoma before. Our data-sets allowed to investigate the dynamic interplay between receptor-triggered kinase activation, phosphorylation events and mRNA-/protein expression changes. While BCR-proximal signaling networks were concordantly regulated among genetically distinct BL cell-types, BCR-distal signaling turned out to be genotype-specific. Based on the detailed signaling information we established genotype-specific kinase/substrate/transcriptome networks that provide functional insights and information about druggable BCR-signaling pathways in BL. Predicted drug targets were furthermore validated in more than twenty BL cell lines using a compound screen that allowed us to correlate BCR signaling profiles with responsiveness to compounds targeting BCR signaling. For instance, heat shock protein 90 (HSP90) inhibition by small molecule inhibitors such as AT13387 induced apoptosis in most analyzed BL cell models and BL xenografts. This was achieved by disruption of BCR signal initiation due to destabilzation of spleen tyrosine kinase expression that turned out to critically depend on HSP90 function in BL. In contrast, compounds like Bruton’s tyrosine kinase and protein kinase B inhibitors targeting the more heterogenous BCR-distal signaling networks induced apoptosis only in certain BL cell-types.
Summary
Taken together our study is a considerable complement to recent genetic studies that elucidated the mutational landscape in BL as it reveals mechanisms of signaling addiction to non-mutated druggable BCR effector proteins. Their further (pre)clinical evaluation as drug targets seems warranted.
Keyword(s): B cell lymphoma, Signal transduction, Targeted therapy
Session topic: Optimization and innovation in treating aggressive lymphomas
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