The UCL Myeloma Laboratory
Group Leader: Prof Kwee Yong
Our work investigates how distinct genetic subgroups of myeloma differ in key biological functions that dictate the clinical outcome of this cancer for patients: cell cycle control, drug resistance and regulation of osteoblast function.
Although this is a slow growing tumour, almost all cases have dysregulated expression of one of the D-type cyclins, which control entry into the cell cycle. In around 50% of cases, this occurs in association with a recurrent IgH translocation, giving rise to a sub-classification of myeloma, based on genetic lesion and the expression of cyclin D1, 2 or 3. This (TC) classification is validated by distinct molecular profiles as well as differences in clinical outcomes. A major aim of our work is to understand how cell cycling and drug resistance of tumour cells is influenced by the type of D-cyclin, and the genetic background.
We have shown that D-type cyclin proteins in myeloma cells are functional and mediate mitogenic effects of growth factors, controlling cell cycling and tumour growth. We have observed that proliferation of tumour cells in response to growth factors, including interleukin-6, insulin-like growth factor-I and A Proliferation Inducing Ligand (APRIL), is dictated by underlying genetic lesions (IgH translocations) and D-type cyclin. Our work thus provides functional validation of the genetic classification of myeloma.
We are currently investigating how the type of D-cyclin expressed influences drug resistance and the response to DNA damage. The presence of myeloma cells in the bone marrow also produces important changes in the bone marrow environment, and one of the most devastating clinically is the un-opposed bone destruction. Up to 70% of patients suffer with bone pain, fractures, and vertebral collapse, resulting in chronic pain and deformity.
Our work seeks to understand the mechanisms of osteoblast suppression, both in vitro and in vivo. We have developed models of myeloma bone disease, and are investigating the early events in stromal cells that lead to the impairment of osteoblast function.
Deepika Kassen (post-doc)
Laura Percy (Clinical Training Fellow)
Dean Smith (Clinical Training Fellow)
Lydia Lee (Clinical Training Fellow – from Mar 2013)
Anna Lach (Technician)
Danton Bounds (Technician)
Prof Asim Khwaja
Dr Martin Pule
Prof John Hartley
Dr David Mann
Rabin N, Percy L, Khan I, Quinn J, D’Sa S, Yong KL (2012) Improved response with post-ASCT consolidation by low dose thalidomide, cyclophosphamide and dexamethasone as first line treatment for multiple myeloma. Br J Haematol 2012 June 19 (epub)
Percy LA, Moore SE, Qian W, Dorman J, Rabin N, Watts M, Linch DC, Yong KL. (2012) Re-infused lymphocyte dose does not influence disease control following upfront autologous stem cell transplantation for multiple myeloma. Br J Haematol; 157:1365
Stengel C, Cheung CW, Quinn J, Yong K, and Khwaja A. Optimal Induction of Myeloma Cell Death Requires Dual Blockade of Phosphoinositide 3-kinase and mTOR Signalling and Is Determined by Translocation Subtype. Leukemia epub (March 14, 2012). http://www.ncbi.nlm.nih.gov/pubmed/22415553.
Glassford J, Kassen D, Quinn J, Stengel C, Kallinikou K, Khwaja A, Yong KL (2011). Inhibition of cell cycle progression by dual phosphatidylinositol-3-kinase and mTOR blockade in cyclin D2 positive multiple myeloma bearing IgH translocations. Blood Cancer Journal e50 doi:10.1038/bcj.2011.44
Quinn, J., Glassford, J., Percy, L., Munson, P., Marafioti, T., Rodriguez-justo, M., Yong, K. (2011). APRIL promotes cell cycle progression in primary multiple myeloma cells: influence of D-type cyclin group and translocation status. Blood 117:890-901
Quinn, J., Percy, L., Glassford, J., Somana, K., Rodriguez-justo, M., Yong, K. (2010). CD20-positive multiple myeloma - differential expression of cyclins D1 and D2 suggests a heterogeneous disease. British Journal of Haematology 149(1), 156-159
Kyriakou, C., Rabin, N., Pizzey, A., Nathwani, A., Yong, K. (2008). Short term homing of human bone marrow derived mesenchymal stem cells (hMSCs) in a xenogeneic animal model is influenced by animal age and is increased by enforced expression of CXCR4. Haematologica 93(10), 1457-1465
Glassford, J., Rabin, N., Lam, E. W., Yong, K. L. (2007). Functional regulation of D-type cyclins by insulin-like growth factor-I and serum in multiple myeloma cells.. Br J Haematol 139(2), 243-254 doi:10.1111/j.1365-2141.2007.06789.x.
Rabin, N., Kyriakou, C., Coulton, L., Gallagher, O. M., Buckle, C., Benjamin, R., Singh, N., Glassford, J., Otsuki, T., Nathwani, A. C., Croucher, P. I., Yong, K. L. (2007). A new xenograft model of myeloma bone disease demonstrating the efficacy of human mesenchymal stem cells expressing osteoprotegerin by lentiviral gene transfer. Leukemia Author URL