Notch Signaling Drives Pathological Osteoclastogenesis in Multiple Myeloma
Faculty Mentor
Jason Ashley
Presentation Type
Oral Presentation
Start Date
5-7-2024 11:10 AM
End Date
5-7-2024 11:30 AM
Location
PAT 328
Primary Discipline of Presentation
Biology
Abstract
Multiple myeloma (MM) is a blood cancer of plasma cells which are mature, antibody-secreting B lymphocytes. In the US, 32,000 new diagnoses of MM and 13,000 deaths associated with MM occur annually. Despite advances in modern oncology, MM remains incurable, demanding further investigation into the underlying biology of the disease. Malignant MM cells migrate to the bone marrow where they dysregulate the normal balance of bone formation and degradation in favor of the latter. This excess degradation of bone leads to higher risk for fragility fracture and further tumor growth through the release of growth factors embedded within mineralized bone. Osteoclasts—cells responsible for bone resorption—become overstimulated in the presence of MM cells. However, the intercellular signaling mechanisms between MM cells and osteoclasts are yet to be thoroughly defined. Of potential consequence is the cell-to-cell signaling pathway, Notch, which is a contact-dependent pathway that requires a ligand-presenting cell and receptor presenting cell. Numerous Notch ligands and receptors exist however the molecular machinery required for allowing all Notch ligands to transmit signal and to receive signal are largely similar. On independent accounts, Notch ligands and receptors have been shown to be overexpressed in malignant MM cells and Notch signaling has been shown to amplify the differentiation and activity of osteoclasts. Herein, using a lentiviral genetic system, we will investigate both the genotypic and phenotypic consequences on osteoclasts when knocking down the genes Mindbomb1—a gene necessary for allowing all Notch ligands to transmit signal—and Mastermind1—a gene necessary for allowing activation of the Notch transcriptional complex—in cocultured MM cells.
Recommended Citation
Ashley, J. W., Ahn, J., & Hankenson, K. D. (2015). Notch Signaling Promotes Osteoclast Maturation and Resorptive Activity. Journal of Cellular Biochemistry, 116(11), 2598–2609. https://doi.org/10.1002/jcb.25205 Colombo, M., Thümmler, K., Mirandola, L., Garavelli, S., Todoerti, K., Apicella, L., Lazzari, E., Lancellotti, M., Platonova, N., Akbar, M., Chiriva-Internati, M., Soutar, R., Neri, A., Goodyear, C. S., & Chiaramonte, R. (n.d.). Notch signaling drives multiple myeloma induced osteoclastogenesis. In Oncotarget (Vol. 5, Issue 21). www.impactjournals.com/oncotarget/ Kopan, R., & Ilagan, M. X. G. (2009). The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism. In Cell (Vol. 137, Issue 2, pp. 216–233). Elsevier B.V. https://doi.org/10.1016/j.cell.2009.03.045 Padala, S. A., Barsouk, A., Barsouk, A., Rawla, P., Vakiti, A., Kolhe, R., Kota, V., & Ajebo, G. H. (2021). Epidemiology, Staging, and Management of Multiple Myeloma. In Medical sciences (Basel, Switzerland) (Vol. 9, Issue 1). NLM (Medline). https://doi.org/10.3390/medsci9010003 Škrtić, A., Korać, P., Krišto, D. R., Ajduković Stojisavljević, R., Ivanković, D., & Dominis, M. (2010). Immunohistochemical analysis of NOTCH1 and JAGGED1 expression in multiple myeloma and monoclonal gammopathy of undetermined significance. Human Pathology, 41(12), 1702–1710. https://doi.org/10.1016/j.humpath.2010.05.002
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Notch Signaling Drives Pathological Osteoclastogenesis in Multiple Myeloma
PAT 328
Multiple myeloma (MM) is a blood cancer of plasma cells which are mature, antibody-secreting B lymphocytes. In the US, 32,000 new diagnoses of MM and 13,000 deaths associated with MM occur annually. Despite advances in modern oncology, MM remains incurable, demanding further investigation into the underlying biology of the disease. Malignant MM cells migrate to the bone marrow where they dysregulate the normal balance of bone formation and degradation in favor of the latter. This excess degradation of bone leads to higher risk for fragility fracture and further tumor growth through the release of growth factors embedded within mineralized bone. Osteoclasts—cells responsible for bone resorption—become overstimulated in the presence of MM cells. However, the intercellular signaling mechanisms between MM cells and osteoclasts are yet to be thoroughly defined. Of potential consequence is the cell-to-cell signaling pathway, Notch, which is a contact-dependent pathway that requires a ligand-presenting cell and receptor presenting cell. Numerous Notch ligands and receptors exist however the molecular machinery required for allowing all Notch ligands to transmit signal and to receive signal are largely similar. On independent accounts, Notch ligands and receptors have been shown to be overexpressed in malignant MM cells and Notch signaling has been shown to amplify the differentiation and activity of osteoclasts. Herein, using a lentiviral genetic system, we will investigate both the genotypic and phenotypic consequences on osteoclasts when knocking down the genes Mindbomb1—a gene necessary for allowing all Notch ligands to transmit signal—and Mastermind1—a gene necessary for allowing activation of the Notch transcriptional complex—in cocultured MM cells.
