Sir Peter MacCallum Department of Oncology - Theses
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ItemTargeting cyclin-dependent kinase 9 and myeloid cell leukaemia 1 in MYC-driven B-cell lymphoma( 2016)Aggressive B-cell lymphomas include diffuse large B-cell lymphoma, Burkitt lymphoma and intermediate forms. Despite high response rates to conventional immuno-chemotherapeutic approaches, an unmet need for novel therapeutic strategies is required in the setting of relapsed and refractory disease, typified by resistance to chemotherapy and radiotherapy. The proto-oncogene MYC is frequently dysregulated in the aggressive B-cell lymphomas, however, it has proven an elusive direct therapeutic target. A significant body of evidence is accumulating to suggest that MYC-dysregulated disease maintains a ‘transcriptionally-addicted’ state, whereby perturbation of RNA polymerase II activity may indirectly antagonise MYC activity. Furthermore, very recent studies implicate anti-apoptotic myeloid cell leukaemia 1 (MCL-1) as a critical survival determinant of MYC-driven lymphoma. This thesis utilises pharmacologic and genetic techniques in MYC-driven models of aggressive B-cell lymphoma to demonstrate that cyclin-dependent kinase 9 (CDK9) and MCL-1 are oncogenic dependencies of this subset of disease. The cyclin-dependent kinase inhibitor, dinaciclib, and more selective CDK9 inhibitors are used to demonstrate efficient apoptosis induction conferred at least in part by downregulation of MCL1 transcription. Furthermore, a genetic screen identifies other transcriptional cyclin-dependent kinases that are required for viability of MYC-driven lymphoid disease. Finally, having established MCL-1 as a critical oncogenic dependency of MYC-driven lymphoma, this thesis demonstrates the significant activity that is conferred by direct pharmacologic antagonism of MCL-1 using a small molecule BH3-mimetic inhibitor of MCL-1. These findings confirm a druggable pathway of oncogenic cMYC dependency involving CDK9 regulated RNA polymerase II-mediated transcription of MCL-1, and proposes pharmacologic inhibition of CDK9 and MCL-1 as novel anti-lymphoma strategies.