Journal article

Potent efficacy of MCL-1 inhibitor-based therapies in preclinical models of mantle cell lymphoma

Michael A Dengler, Charis E Teh, Rachel Thijssen, Lahiru Gangoda, Ping Lan, Marco J Herold, Daniel H Gray, Gemma L Kelly, Andrew W Roberts, Jerry M Adams

Oncogene | NATURE PUBLISHING GROUP | Published : 2020

Abstract

Apoptosis-regulating BCL-2 family members, which can promote malignant transformation and resistance to therapy, have become prime therapeutic targets, as illustrated by the striking efficacy in certain lymphoid malignancies of the BCL-2-specific inhibitor venetoclax. In other lymphoid malignancies, however, such as the aggressive mantle cell lymphoma (MCL), cell survival might rely instead or also on BCL-2 relative MCL-1. We have explored MCL-1 as a target for killing MCL cells by both genetic and pharmacologic approaches. In several MCL cell lines, MCL-1 knockout with an inducible CRISPR/Cas9 system triggered spontaneous apoptosis. Accordingly, most MCL cell lines proved sensitive to the s..

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Grants

Awarded by CASS Foundation Science Medicine Grant


Awarded by National Health and Medical Research Council (NHMRC)


Awarded by SCOR from the Leukemia and Lymphoma Society


Awarded by NHMRC


Awarded by Victorian Cancer Agency Fellowship


Awarded by Cancer Council of Victoria


Awarded by Australian Government Independent Research Institute Infrastructure Support Scheme


Funding Acknowledgements

We thank Naomi Sprigg (Royal Melbourne Hospital) for assistance with fresh clinical samples, Leonie Gibson and Tania Tan for excellent technical assistance, and Connie Li Wai Suen for statistical advice. We would like to acknowledge the Metro South Health Cancer Collaborative Biobank, Brisbane for the provision of hematologic malignancy samples for this project. The Cancer Collaborative Biobank is supported by Metro South Health funding. This work was supported by a CASS Foundation Science & Medicine Grant SM/18/7801 (to MAD); program grant 1016701 (to JMA) and Practitioner Fellowship 1079560 (to AWR) from the National Health and Medical Research Council (NHMRC); SCOR grant 7015-18 (to JMA and AWR) and Fellowship 5467-18 (to RT) from the Leukemia and Lymphoma Society; NHMRC Fellowship 1089072 (to CET), NHMRC Fellowship 1090236 (to DHG), Victorian Cancer Agency Fellowship MCRF 17028 (to GLK), Cancer Council of Victoria Grants-in-Aid 1146518 (to DHG) and 1147328 (to GLK), Leukaemia Foundation Australia grant (to GLK), and operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (9000220) and the Victorian State Government Operational Infrastructure Support Program. This work was performed in part at the Materials Characterization and Fabrication Platform at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility.