Quinn, J; (2013) The Role of APRIL in Promoting Cell Cycle Progression and Drug Resistance in Multiple Myeloma. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Recent years have seen a significant improvement in survival for patients with multiple myeloma (MM). Novel agent-based induction regimens have resulted in dramatically high overall response rates, however, the overwhelming majority of patients relapse and MM remains incurable. Furthermore, MM shows considerable clinical heterogeneity and patients with “high-risk” MM continue to fare badly even with novel therapies. Thus, identifying the key factors that are responsible for the proliferation of MM cells is a critical step in further improving outcomes for MM patients. It has been extensively shown that bone marrow (BM) microenvironmental factors promote MM cell proliferation, survival and drug resistance. The tumour necrosis factor superfamily member, A Proliferation-Inducing Ligand (APRIL) has recently been shown to be a survival factor for normal plasma cells and to promote drug resistance in IL-6 dependent MM cell lines. Therefore, the overall aim of this work was to examine the role of APRIL in MM and in particular, to determine whether APRIL could induce cell cycle progression in primary MM cells. In summary, APRIL was found to promote cell cycle progression in primary MM cells, but this effect was restricted to those cells expressing cyclin D2 and carrying the t(4;14) and t(14;16) translocations, in contrast to cyclin D1-expressing MM cells that were less responsive. In addition APRIL was found to protect cyclin D2-expressing MM cells from drug-induced apoptosis. Cell surface receptors for APRIL were found to be present on the surfaces of primary MM cells and APRIL was shown to be abundant in the myeloma BM microenvironment. In conclusion, these results show that cell cycle responses to APRIL segregate with respect to D-type cyclin class and translocation status and and pave the way for future mechanistic studies, as well as providing a rationale for designing specific therapies for different genetic subgroups of patients.

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