title: Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1.
abstract: New therapeutic targets are needed to address the poor prognosis of patients with high-risk multiple myeloma. Myeloma cells usually express a range of the prosurvival BCL2 proteins. To define the hierarchy of their relative importance for maintaining the survival of myeloma cells, we targeted each of them in a large panel of cell lines, using pharmacological inhibitors or gene editing or by peptide-based approaches, alone or in combination. The majority of well-established immortalized cell lines (17/25) or low-passage myeloma cell lines (5/7) are readily killed when MCL1 is targeted, even including those cell lines sensitive to BCL2 inhibition. Targeting MCL1 also constrained the growth of myeloma in vivo. We also identified a previously unrecognized subset of myeloma that is highly BCLXL-dependent, and has the potential for cotargeting MCL1 and BCLXL. As MCL1 is pivotal for maintaining survival of most myelomas, it should be prioritized for targeting in the clinic once high-quality, validated inhibitors become available.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Australia.
authors.forename: Jia-Nan
authors.identifier: 0000-0002-6554-1815
authors.initials: JN
authors.lastname: Gong
authors.affiliation: Myeloma Research Group, Australian Centre for Blood Diseases, Monash University and the Alfred Hospital, Melbourne, Australia.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Khong
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Australia.
authors.forename: David
authors.identifier: 0000-0003-4003-4515
authors.initials: D
authors.lastname: Segal
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Australia.|School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Chris D
authors.initials: CD
authors.lastname: Riffkin
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Australia.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Garnier
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Australia.|Royal Children's Hospital, Melbourne, Australia.
authors.forename: Seong Lin
authors.initials: SL
authors.lastname: Khaw
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Australia.|Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Australia.
authors.forename: Guillaume
authors.identifier: 0000-0002-1193-8147
authors.initials: G
authors.lastname: Lessene
authors.affiliation: Myeloma Research Group, Australian Centre for Blood Diseases, Monash University and the Alfred Hospital, Melbourne, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Australia.
authors.forename: Marco J
authors.identifier: 0000-0001-7539-7581
authors.initials: MJ
authors.lastname: Herold
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Australia.|Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Melbourne, Australia; and.|Victorian Comprehensive Cancer Centre, Parkville, Australia.
authors.forename: Andrew W
authors.identifier: 0000-0002-7341-5720
authors.initials: AW
authors.lastname: Roberts
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Australia.
authors.forename: David C S
authors.identifier: 0000-0002-3101-4873
authors.initials: DCS
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064113:CRISPR-Cas Systems / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000072669:Gene Editing; D006801:Humans; D008024:Ligands; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D054852:Small Molecule Libraries