Contributions
Abstract: EP956
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Biology & Translational Research
Background
There is a gap in our understanding of the molecular mechanisms behind the chemoresistance seen in early multiple myeloma (MM) patients who receive standard treatment (i.e. Lenalidomide/revlimid, Bortezomib/velcade, and Dexamethasone (RVD)). The reason for the relatively high percentage of patients that progress after early RVD treatment is unknown. Therefore, the identification of clinically relevant clusters of co-expressed genes or biomarkers for MM progression in patients on RVD treatment would help identify novel mechanisms, drug targets, and prognostic markers.
Aims
Aim 1 will establish the clinical significance of BDKRB1, and associated genes co-expressed during MM progression.
Aim 2 will determine the molecular mechanisms by which bradykinin-BDKRB1 signaling affects MM cell growth and chemoresistance.
Methods
In this project, we employed a transcriptomic analysis approach to identify hub genes that correlate with MM progression and RVD chemoresistance. One of the most significantly expressed hub genes identified was the bradykinin receptor B1 (BDKRB1) gene, a G protein-coupled receptor. BDKRB1-signaling has been demonstrated in cell adhesion, signal transduction, and calcium flux, all of which can promote MM progression. The specific role of BDKRB1 in MM is undefined; therefore, an understanding of the molecular mechanisms mediated by BDKRB1 interactions in MM patients is urgently needed. To this end, we investigated the gene expression profiles and their correlation with MM clinical outcomes, using a novel weighted gene network co-expression analysis (WGCNA) method.
Results
WGCNA constructed 21 modules using the MMRF COMMpass dataset (n = 175) based on gene co-expression correlations between RVD treatment and age at diagnosis and/or death. The grey60 module contained BDKRB1 and 247 other upregulated co-expressed genes, which were significantly and positively correlated (p < 9.7E-07, R2 =0.38) with MM progression following initial RVD treatment. The top biological processes associated with this module include the G protein-coupled receptor protein signaling pathway, calcium influx, inflammatory response, regulation of growth, and biological adhesion. Notably, gene expression driven by NF-Kβ is known to be activated by the bradykinin-BDKRB1 signaling axis, which significantly correlates with the lethal molecular subset of MM, MM proliferation and patient survival. The receiver operator characteristic (ROC) curve analysis predicted BDKRB1 as a statistically significant biomarker for MM progression (p-values=0.00016).
Conclusion
Our preliminary studies showed BDKRB1-signaling networks are significantly co-expressed and associated with MM progression. This is the first study to identify BDKRB1-associated gene networks and analyze their potential impact on MM progression. BDKRB1 is highly expressed in African Americans. AA is known to be 3 to 4-fold more likely to develop MM. Hence, the completion of my projects may shed new light on the impact of bradykinin-BDKRB1 signaling in MM progression, and RVD chemoresistance, and MM health disparities
Keyword(s):
Abstract: EP956
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Biology & Translational Research
Background
There is a gap in our understanding of the molecular mechanisms behind the chemoresistance seen in early multiple myeloma (MM) patients who receive standard treatment (i.e. Lenalidomide/revlimid, Bortezomib/velcade, and Dexamethasone (RVD)). The reason for the relatively high percentage of patients that progress after early RVD treatment is unknown. Therefore, the identification of clinically relevant clusters of co-expressed genes or biomarkers for MM progression in patients on RVD treatment would help identify novel mechanisms, drug targets, and prognostic markers.
Aims
Aim 1 will establish the clinical significance of BDKRB1, and associated genes co-expressed during MM progression.
Aim 2 will determine the molecular mechanisms by which bradykinin-BDKRB1 signaling affects MM cell growth and chemoresistance.
Methods
In this project, we employed a transcriptomic analysis approach to identify hub genes that correlate with MM progression and RVD chemoresistance. One of the most significantly expressed hub genes identified was the bradykinin receptor B1 (BDKRB1) gene, a G protein-coupled receptor. BDKRB1-signaling has been demonstrated in cell adhesion, signal transduction, and calcium flux, all of which can promote MM progression. The specific role of BDKRB1 in MM is undefined; therefore, an understanding of the molecular mechanisms mediated by BDKRB1 interactions in MM patients is urgently needed. To this end, we investigated the gene expression profiles and their correlation with MM clinical outcomes, using a novel weighted gene network co-expression analysis (WGCNA) method.
Results
WGCNA constructed 21 modules using the MMRF COMMpass dataset (n = 175) based on gene co-expression correlations between RVD treatment and age at diagnosis and/or death. The grey60 module contained BDKRB1 and 247 other upregulated co-expressed genes, which were significantly and positively correlated (p < 9.7E-07, R2 =0.38) with MM progression following initial RVD treatment. The top biological processes associated with this module include the G protein-coupled receptor protein signaling pathway, calcium influx, inflammatory response, regulation of growth, and biological adhesion. Notably, gene expression driven by NF-Kβ is known to be activated by the bradykinin-BDKRB1 signaling axis, which significantly correlates with the lethal molecular subset of MM, MM proliferation and patient survival. The receiver operator characteristic (ROC) curve analysis predicted BDKRB1 as a statistically significant biomarker for MM progression (p-values=0.00016).
Conclusion
Our preliminary studies showed BDKRB1-signaling networks are significantly co-expressed and associated with MM progression. This is the first study to identify BDKRB1-associated gene networks and analyze their potential impact on MM progression. BDKRB1 is highly expressed in African Americans. AA is known to be 3 to 4-fold more likely to develop MM. Hence, the completion of my projects may shed new light on the impact of bradykinin-BDKRB1 signaling in MM progression, and RVD chemoresistance, and MM health disparities
Keyword(s):