CONSTITUTIVE GSK-3B ACTIVATION INDUCED Β-CATENIN DEREGULATION IN CLASSICAL HODGKIN LYMPHOMA PATIENTS
(Abstract release date: 05/19/16)
EHA Library. De Matteis S. 06/09/16; 132948; E1399
Dr. Serena De Matteis
Contributions
Contributions
Abstract
Abstract: E1399
Type: Eposter Presentation
Background
Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase involved in glycogen metabolism, in cell cycle progression, differentiation and embryogenesis.One of the major biological functions of GSK-3β is to inhibit β-catenin by sequestration and promotion of its proteasomal degradation in the Wnt canonical pathway. Aberrant GSK-3β has been implicated in the pathogenesis of many disorders such as diabetes, Alzheimer’s and Parkinson’s disease and cancer. The biological role of GSK-3β in classical Hodgkin lymphoma (cHL) has not yet been clarified.
Aims
The aim of this study is to clarify the biological relevance of GSK-3β in the regulation of the β-catenin in cHL.
Methods
Three tissue microarrays (TMA) for immunohistochemical studies were obtained from formalin-fixed paraffin-embedded samples collected at diagnosis from 100 cHL patients. TMA sections were investigated by antibodies reactive with pY216 and pS9 GSK-3β and β-catenin. Three samples of hyperplastic lymph nodes were added to investigate the expression of the same markers in the reactive lymphoid tissue. Immunohistochemical preparations were visualized and images were captured using Olympus Dot-slide microscope digital system equipped with the VS110 image analysis software.
Results
Our results showed that the pY216 GSK3β, which is the stimulatory form of the kinase, was observed in 100% of cHL cases with a range of positivity in the neoplastic population from 8% to 100% and a mean expression of 56%. In 78/100 cases, we noticed that the kinase was predominantly relocated in the nucleus of the Hodgkin and Reed-Sternberg cells (Figure A), in which it is expected to be highly active. Conversely, the germinal centres of the reactive follicles showed a weak cytoplasmic positivity of the stimulatory pGSK-3β. Moreover, 20 samples were assessed positive for the inhibitory form pS9 GSK-3β with a range of positivity from 1% to 58% and a mean expression of 8%. β-catenin was detected only in 12% of the cases with a nuclear localization (Figure B). Interestingly, a statistically significant association between the presence of β-catenin in the nucleus and the inhibitory pGSK-3β expression was observed (P = 0.013).
Conclusion
Our results reported the constitutive activation of the stimulatory pGSK-3β that plays a previously unrecognized important role in the negative regulation of β-catenin transcription activity in cHL cells, by affecting its binding to the promoters of a subset of related-target genes. GSK-3β is an intriguing protein that seems to be involved in the pathogenesis of cHL, but many questions remain unanswered and the role of GSK-3β and its potential application in this disease become an interesting aspect to clarify. These data suggest GSK-3β as a promising novel target for therapeutic intervention in cHL.
Session topic: E-poster
Keyword(s): Beta-catenin, Hodgkin's lymphoma, Phosphorylation
Type: Eposter Presentation
Background
Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase involved in glycogen metabolism, in cell cycle progression, differentiation and embryogenesis.One of the major biological functions of GSK-3β is to inhibit β-catenin by sequestration and promotion of its proteasomal degradation in the Wnt canonical pathway. Aberrant GSK-3β has been implicated in the pathogenesis of many disorders such as diabetes, Alzheimer’s and Parkinson’s disease and cancer. The biological role of GSK-3β in classical Hodgkin lymphoma (cHL) has not yet been clarified.
Aims
The aim of this study is to clarify the biological relevance of GSK-3β in the regulation of the β-catenin in cHL.
Methods
Three tissue microarrays (TMA) for immunohistochemical studies were obtained from formalin-fixed paraffin-embedded samples collected at diagnosis from 100 cHL patients. TMA sections were investigated by antibodies reactive with pY216 and pS9 GSK-3β and β-catenin. Three samples of hyperplastic lymph nodes were added to investigate the expression of the same markers in the reactive lymphoid tissue. Immunohistochemical preparations were visualized and images were captured using Olympus Dot-slide microscope digital system equipped with the VS110 image analysis software.
Results
Our results showed that the pY216 GSK3β, which is the stimulatory form of the kinase, was observed in 100% of cHL cases with a range of positivity in the neoplastic population from 8% to 100% and a mean expression of 56%. In 78/100 cases, we noticed that the kinase was predominantly relocated in the nucleus of the Hodgkin and Reed-Sternberg cells (Figure A), in which it is expected to be highly active. Conversely, the germinal centres of the reactive follicles showed a weak cytoplasmic positivity of the stimulatory pGSK-3β. Moreover, 20 samples were assessed positive for the inhibitory form pS9 GSK-3β with a range of positivity from 1% to 58% and a mean expression of 8%. β-catenin was detected only in 12% of the cases with a nuclear localization (Figure B). Interestingly, a statistically significant association between the presence of β-catenin in the nucleus and the inhibitory pGSK-3β expression was observed (P = 0.013).
Conclusion
Our results reported the constitutive activation of the stimulatory pGSK-3β that plays a previously unrecognized important role in the negative regulation of β-catenin transcription activity in cHL cells, by affecting its binding to the promoters of a subset of related-target genes. GSK-3β is an intriguing protein that seems to be involved in the pathogenesis of cHL, but many questions remain unanswered and the role of GSK-3β and its potential application in this disease become an interesting aspect to clarify. These data suggest GSK-3β as a promising novel target for therapeutic intervention in cHL.
Session topic: E-poster
Keyword(s): Beta-catenin, Hodgkin's lymphoma, Phosphorylation
Abstract: E1399
Type: Eposter Presentation
Background
Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase involved in glycogen metabolism, in cell cycle progression, differentiation and embryogenesis.One of the major biological functions of GSK-3β is to inhibit β-catenin by sequestration and promotion of its proteasomal degradation in the Wnt canonical pathway. Aberrant GSK-3β has been implicated in the pathogenesis of many disorders such as diabetes, Alzheimer’s and Parkinson’s disease and cancer. The biological role of GSK-3β in classical Hodgkin lymphoma (cHL) has not yet been clarified.
Aims
The aim of this study is to clarify the biological relevance of GSK-3β in the regulation of the β-catenin in cHL.
Methods
Three tissue microarrays (TMA) for immunohistochemical studies were obtained from formalin-fixed paraffin-embedded samples collected at diagnosis from 100 cHL patients. TMA sections were investigated by antibodies reactive with pY216 and pS9 GSK-3β and β-catenin. Three samples of hyperplastic lymph nodes were added to investigate the expression of the same markers in the reactive lymphoid tissue. Immunohistochemical preparations were visualized and images were captured using Olympus Dot-slide microscope digital system equipped with the VS110 image analysis software.
Results
Our results showed that the pY216 GSK3β, which is the stimulatory form of the kinase, was observed in 100% of cHL cases with a range of positivity in the neoplastic population from 8% to 100% and a mean expression of 56%. In 78/100 cases, we noticed that the kinase was predominantly relocated in the nucleus of the Hodgkin and Reed-Sternberg cells (Figure A), in which it is expected to be highly active. Conversely, the germinal centres of the reactive follicles showed a weak cytoplasmic positivity of the stimulatory pGSK-3β. Moreover, 20 samples were assessed positive for the inhibitory form pS9 GSK-3β with a range of positivity from 1% to 58% and a mean expression of 8%. β-catenin was detected only in 12% of the cases with a nuclear localization (Figure B). Interestingly, a statistically significant association between the presence of β-catenin in the nucleus and the inhibitory pGSK-3β expression was observed (P = 0.013).
Conclusion
Our results reported the constitutive activation of the stimulatory pGSK-3β that plays a previously unrecognized important role in the negative regulation of β-catenin transcription activity in cHL cells, by affecting its binding to the promoters of a subset of related-target genes. GSK-3β is an intriguing protein that seems to be involved in the pathogenesis of cHL, but many questions remain unanswered and the role of GSK-3β and its potential application in this disease become an interesting aspect to clarify. These data suggest GSK-3β as a promising novel target for therapeutic intervention in cHL.
Session topic: E-poster
Keyword(s): Beta-catenin, Hodgkin's lymphoma, Phosphorylation
Type: Eposter Presentation
Background
Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase involved in glycogen metabolism, in cell cycle progression, differentiation and embryogenesis.One of the major biological functions of GSK-3β is to inhibit β-catenin by sequestration and promotion of its proteasomal degradation in the Wnt canonical pathway. Aberrant GSK-3β has been implicated in the pathogenesis of many disorders such as diabetes, Alzheimer’s and Parkinson’s disease and cancer. The biological role of GSK-3β in classical Hodgkin lymphoma (cHL) has not yet been clarified.
Aims
The aim of this study is to clarify the biological relevance of GSK-3β in the regulation of the β-catenin in cHL.
Methods
Three tissue microarrays (TMA) for immunohistochemical studies were obtained from formalin-fixed paraffin-embedded samples collected at diagnosis from 100 cHL patients. TMA sections were investigated by antibodies reactive with pY216 and pS9 GSK-3β and β-catenin. Three samples of hyperplastic lymph nodes were added to investigate the expression of the same markers in the reactive lymphoid tissue. Immunohistochemical preparations were visualized and images were captured using Olympus Dot-slide microscope digital system equipped with the VS110 image analysis software.
Results
Our results showed that the pY216 GSK3β, which is the stimulatory form of the kinase, was observed in 100% of cHL cases with a range of positivity in the neoplastic population from 8% to 100% and a mean expression of 56%. In 78/100 cases, we noticed that the kinase was predominantly relocated in the nucleus of the Hodgkin and Reed-Sternberg cells (Figure A), in which it is expected to be highly active. Conversely, the germinal centres of the reactive follicles showed a weak cytoplasmic positivity of the stimulatory pGSK-3β. Moreover, 20 samples were assessed positive for the inhibitory form pS9 GSK-3β with a range of positivity from 1% to 58% and a mean expression of 8%. β-catenin was detected only in 12% of the cases with a nuclear localization (Figure B). Interestingly, a statistically significant association between the presence of β-catenin in the nucleus and the inhibitory pGSK-3β expression was observed (P = 0.013).
Conclusion
Our results reported the constitutive activation of the stimulatory pGSK-3β that plays a previously unrecognized important role in the negative regulation of β-catenin transcription activity in cHL cells, by affecting its binding to the promoters of a subset of related-target genes. GSK-3β is an intriguing protein that seems to be involved in the pathogenesis of cHL, but many questions remain unanswered and the role of GSK-3β and its potential application in this disease become an interesting aspect to clarify. These data suggest GSK-3β as a promising novel target for therapeutic intervention in cHL.
Session topic: E-poster
Keyword(s): Beta-catenin, Hodgkin's lymphoma, Phosphorylation
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