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Precision Medicine

A Therapeutic Target for Multiple Myeloma-Related Bone Disease

Integrin α6 is a Novel Potential Therapeutic Target for Multiple Myeloma-Associated Osteolytic Lesions
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Researchers at Houston Methodist have identified integrin α6 as a potential therapeutic target for bone healing in multiple myeloma (MM) patients. Using cell lines, primary myeloma cells and murine models, Jing Yang, PhD, associate professor of oncology, investigated the intercellular communication between myeloma cells and mesenchymal stem cells (MSCs) mediated by integrin α6. The results of this research study are published in Frontiers in Oncology in 2021. As the second most common blood cancer in the United States, MM is predicted to account for 34,470 new cases in 2022, according to the American Cancer Society. MM symptoms include kidney injury, anemia, hypercalcemia as well as osteolytic lesions. Greater than 80% of MM patients experience skeleton-related events, including pathological fracture, severe bone pain, spinal cord compression and hypercalcemia. The pathogenesis of MM-associated bone disease is complex since the bone marrow microenvironment is rife with osteoblasts, osteoclasts and stromal cells engaged in extensive intercellular communication. A precise balance between osteoblastic (bone formation) and osteoclastic (bone resorption) activity maintains a healthy bone structure and prevents diseases such as osteoporosis.
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Jing Yang, PhD Associate Professor of Oncology at Houston Methodist
The bone marrow of MM patients carries abnormal clonal plasma cells that have the potential for uncontrolled proliferation. The current treatment for MM patients with bone disease includes drugs such as bisphosphonates which aim to mitigate bone loss and improve the quality of life of MM patients. However, bisphosphonates are not curative and hence more effective therapies are urgently needed. Yang has contributed to a better understanding of the tumor-bone microenvironment that is crucial for the development of novel therapeutics for MM. Specifically, Yang’s research suggests formation of a trimer complex between integrin α6 on myeloma cells, laminin 8 on myeloma cells and epidermal growth factor receptor (EGFR) on mesenchymal stem cells (MSCs). This triggers a cascade of signaling events leading to osteolytic cytokine expression in both myeloma cells and MSCs. The homeostatic balance between osteoblastogenesis and osteoclastogenesis prevalent in the healthy bone marrow microenvironment is disrupted in the case of MM. Integrin family members are known to play a role in myeloma-induced bone lesions. A distinct role of integrin α6 has been illustrated in Yang’s study.
Our study for the first time demonstrates the integrin α6-laminin 8-EGFR complex that links myeloma cells and mesenchymal stem cells and contributes to myeloma-induced osteolytic bone lesions. Our results elucidate a new mechanism by which myeloma-mesenchymal stem cell interaction upregulates the production of osteolytic cytokines through the integrin α6/laminin8/EGFR signaling and offer a potential strategy for targeted treatment of myeloma-associated bone disease
Jing Yang, PhD
Associate Professor of Oncology at Houston Methodist
According to Yang, “Our study for the first time demonstrates the integrin α6-laminin 8-EGFR complex that links myeloma cells and mesenchymal stem cells and contributes to myeloma-induced osteolytic bone lesions. Our results elucidate a new mechanism by which myeloma-mesenchymal stem cell interaction upregulates the production of osteolytic cytokines through the integrin α6/laminin8/EGFR signaling and offer a potential strategy for targeted treatment of myeloma-associated bone disease.” Further research towards a deeper dive into the MSC-myeloma cell interactions as well as the signaling pathways triggered by integrin α-induced signaling may aid in creating therapeutic improvements to enhance the quality of life of MM patients.
Huan Liu, Zhiming Wang, Jin He, Zongwei Li, Jerry Y Gao, Rui Liu, Pei Lin, Jing Yang. Promotion of Bone Lesions Through the Myeloma Integrin α6-Mediated Osteolytic Signaling. Front Oncol.2021 Jun 3;11:692190. This research was supported by the National Institutes of Health/National Cancer Institute (R01 awards CA190863 and CA193362).
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Abanti Chattopadhyay, PhD
March 2023
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