Abstract
Original language | English |
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Pages (from-to) | 754-773 |
Number of pages | 20 |
Journal | Nature Cancer |
Volume | 4 |
Issue number | 5 |
DOIs | |
Publication status | Published - 1 May 2023 |
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In: Nature Cancer, Vol. 4, No. 5, 01.05.2023, p. 754-773.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Genome-scale functional genomics identify genes preferentially essential for multiple myeloma cells compared to other neoplasias
AU - de Matos Simoes, Ricardo
AU - Shirasaki, Ryosuke
AU - Downey-Kopyscinski, Sondra L.
AU - Matthews, Geoffrey M.
AU - Barwick, Benjamin G.
AU - Gupta, Vikas A.
AU - Dupéré-Richer, Daphné
AU - Yamano, Shizuka
AU - Hu, Yiguo
AU - Sheffer, Michal
AU - Dhimolea, Eugen
AU - Dashevsky, Olga
AU - Gandolfi, Sara
AU - Ishiguro, Kazuya
AU - Meyers, Robin M.
AU - Bryan, Jordan G.
AU - Dharia, Neekesh V.
AU - Hengeveld, Paul J.
AU - Brüggenthies, Johanna B.
AU - Tang, Huihui
AU - Aguirre, Andrew J.
AU - Sievers, Quinlan L.
AU - Ebert, Benjamin L.
AU - Glassner, Brian J.
AU - Ott, Christopher J.
AU - Bradner, James E.
AU - Kwiatkowski, Nicholas P.
AU - Auclair, Daniel
AU - Levy, Joan
AU - Keats, Jonathan J.
AU - Groen, Richard W. J.
AU - Gray, Nathanael S.
AU - Culhane, Aedin C.
AU - McFarland, James M.
AU - Dempster, Joshua M.
AU - Licht, Jonathan D.
AU - Boise, Lawrence H.
AU - Hahn, William C.
AU - Vazquez, Francisca
AU - Tsherniak, Aviad
AU - Mitsiades, Constantine S.
N1 - Funding Information: This work was supported by grants NIH R01 CA050947 (C.S.M.), CA179483 (C.S.M.), CA196664 (C.S.M. and R.W.J.G.), R01CA276156 (C.S.M.), CA180475 (J.D.L. and C.S.M.), CA192844 (L.H.B.), U01CA225730 (C.S.M.) and U01CA176058 (W.C.H); and by the de Gunzburg Myeloma Research Fund (C.S.M.), Leukemia and Lymphoma Society (LLS) Translational Research Program (C.S.M.), LLS Quest for Cure Program (C.S.M. and R.W.J.G.), LLS Scholar Award (C.S.M.), LLS Specialized Center for Research (J.D.L.), LLS Special Fellow Award (D.D.R.), Multiple Myeloma Research Foundation (MMRF) Answer Fund (C.S.M., J.D.L. and L.H.B.), MMRF Translational Network of Excellence (C.S.M.), MMRF Epigenetics Program Project grant (J.D.L. and C.S.M.), Shawna Ashlee Corman Investigatorship in Multiple Myeloma Research (C.S.M.), Cobb Family Myeloma Research Fund (C.S.M.), Paula and Rodger Riney Foundation (L.H.B.), Chambers Family Advanced Myeloma Research Fund (C.S.M.), International Waldenstrom’s Macroglobulinemia Foundation (C.S.M.), Department of Defense grant W81XWH-15-1-0012 (A.C. and C.S.M.), International Myeloma Foundation (G.M.M.), American-Australian Association (G.M.M.), Associazione Italiana per la Ricerca sul Cancro (S.G.), Claudia Adams Barr Program in Innovative Basic Cancer Research at Dana-Farber Cancer Institute (M.S., E.D. and C.S.M.), Dutch Cancer Society grant VU2011-5127 (R.W.J.G.) and Ludwig Center at Harvard (C.S.M.). Q.L.S. was supported by award number T32GM007753 from the National Institute of General Medical Sciences. B.G.B. was supported by an MMRF Research Fellow Award and an ASH Research Scholar Award. V.A.G. was supported by the American Cancer Society grant #IRG-14-188-01 to the Winship Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. The authors thank S. Sarkar, M. A. Bariteau and M. Borah for technical assistance in experiments related to this study and J. Sorrell for administrative coordination. The authors apologize in advance for the inability to reference in our paper all possible studies in the literature that are directly relevant to our findings. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - Clinical progress in multiple myeloma (MM), an incurable plasma cell (PC) neoplasia, has been driven by therapies that have limited applications beyond MM/PC neoplasias and do not target specific oncogenic mutations in MM. Instead, these agents target pathways critical for PC biology yet largely dispensable for malignant or normal cells of most other lineages. Here we systematically characterized the lineage-preferential molecular dependencies of MM through genome-scale clustered regularly interspaced short palindromic repeats (CRISPR) studies in 19 MM versus hundreds of non-MM lines and identified 116 genes whose disruption more significantly affects MM cell fitness compared with other malignancies. These genes, some known, others not previously linked to MM, encode transcription factors, chromatin modifiers, endoplasmic reticulum components, metabolic regulators or signaling molecules. Most of these genes are not among the top amplified, overexpressed or mutated in MM. Functional genomics approaches thus define new therapeutic targets in MM not readily identifiable by standard genomic, transcriptional or epigenetic profiling analyses.
AB - Clinical progress in multiple myeloma (MM), an incurable plasma cell (PC) neoplasia, has been driven by therapies that have limited applications beyond MM/PC neoplasias and do not target specific oncogenic mutations in MM. Instead, these agents target pathways critical for PC biology yet largely dispensable for malignant or normal cells of most other lineages. Here we systematically characterized the lineage-preferential molecular dependencies of MM through genome-scale clustered regularly interspaced short palindromic repeats (CRISPR) studies in 19 MM versus hundreds of non-MM lines and identified 116 genes whose disruption more significantly affects MM cell fitness compared with other malignancies. These genes, some known, others not previously linked to MM, encode transcription factors, chromatin modifiers, endoplasmic reticulum components, metabolic regulators or signaling molecules. Most of these genes are not among the top amplified, overexpressed or mutated in MM. Functional genomics approaches thus define new therapeutic targets in MM not readily identifiable by standard genomic, transcriptional or epigenetic profiling analyses.
UR - http://www.scopus.com/inward/record.url?scp=85160376656&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s43018-023-00550-x
DO - https://doi.org/10.1038/s43018-023-00550-x
M3 - Article
C2 - 37237081
SN - 2662-1347
VL - 4
SP - 754
EP - 773
JO - Nature Cancer
JF - Nature Cancer
IS - 5
ER -