Group Leader: Professor 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. Moreover, 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. We have also shown that cyclin D2 expressing myeloma cells are particularly sensitive to PI3k inhibition, and are exploring the clinical implication of this in a phase 1 study of a pan-PI3k inhibitor in defined genetic subgroups of myeloma patients (Bloodwise funded NCRN BUBBLE study). Related to our work on the APRIL pathway in myeloma, we are developing BCMA-targeted translational strategies.
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, and we are investigating the early events in stromal cells that lead to the impairment of osteoblast function. Alongside this, we are also studying the immune environment in the bone marrow as a means to understand the contribution of immune mechanisms to disease control.
Lee L, Bounds D, Paterson J, Herledan G, Sully K, Seestaller-Wehr L M, Fieles W E, Tunstead J, Germaschewski F, Mayes P, Craigen J, Yong KL. (2016) Evaluation of B Cell Maturation Antigen as a Target for Antibody Drug Conjugate Mediated Cytotoxicity in Multiple Myeloma. British Journal of Haematology, 17 June 2016. doi:10.1111/bjh.14145.
Kassen D, Lath D, Lach A, Evans H, Chantry A, Rabin N, Croucher P, and Yong KL. (2016) Myeloma Impairs Mature Osteoblast Function but Causes Early Expansion of Osteo-Progenitors: Temporal Changes in Bone Physiology and Gene Expression in the KMS12BM Model. British Journal of Haematology 172:64-79
Smith, Dean, David Mann, and Kwee Yong. (2016) Cyclin D Type Does Not Influence Cell Cycle Response to DNA Damage Caused by Ionizing Radiation in Multiple Myeloma Tumours. British Journal of Haematology 173, no. 5 (June 2016): 693–704. doi:10.1111/bjh.13982.
Sive, Jonathan I., Andrew Feber, Dean Smith, John Quinn, Stephan Beck, and Kwee Yong. (2016) ‘Global Hypomethylation in Myeloma Is Associated with Poor Prognosis’. British Journal of Haematology 172, no. 3 (February 2016): 473–75. doi:10.1111/bjh.13506.
Smith D, Armenteros E, Percy L, Kumar M, Lach A, Herledan G, Stubbs M, Downward J, and Yong KL. (2015) RAS Mutation Status and Bortezomib Therapy for Relapsed Multiple Myeloma. British Journal of Haematology 169, no. 6 (June 2015): 905–8. doi:10.1111/bjh.13258.
Kassen D, Moore S, Percy L, Herledan G, Bounds D, Rodriguez-Justo M, Yong KL. (2014) The bone marrow stromal compartment in multiple myeloma patients retains capability for osteogenic differentiation in vitro: defining the stromal defect in myeloma. British Journal of Haematology 167: 194-206
**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) Pubmed
**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. (2012) Optimal Induction of Myeloma Cell Death Requires Dual Blockade of Phosphoinositide 3-kinase and mTOR Signalling and Is Determined by Translocation Subtype. Leukemia 26:1761-1770.
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. British Journal of Haematology 139(2), 243-254
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 21:2181-2191