Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
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(Published version)
Date
2023
Authors
Kan, W.L.
Dhagat, U.
Hercus, T.R.
Kaufmann, K.B.
Nero, T.L.
Zeng, A.G.X.
Toubia, J.
Barry, E.F.
Broughton, S.E.
Gomez, G.A.
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Journal Title
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Journal article
Citation
Cancer Discovery, 2023; 13(8):1922-1947
Statement of Responsibility
Winnie L. Kan, Urmi Dhagat, Kerstin B. Kaufmann, Timothy R. Hercus, Tracy L. Nero, Andy G.X. Zeng, John Toubia, Emma F. Barry, Sophie E. Broughton, Guillermo A. Gomez, Brooks A. Benard, Mara Dottore, Karen S. Cheung Tung Shing, Héléna Boutzen, Saumya E. Samaraweera, Kaylene J. Simpson, Liqing Jin, Gregory J. Goodall, C. Glenn Begley, Daniel Thomas, Paul G. Ekert, Denis Tvorogov, Richard J. D, Andrea, John E. Dick, Michael W. Parker, and Angel F. Lopez
Conference Name
Abstract
Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance.
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Published first May 16, 2023
Data source: Supplementary data, https://doi.org/10.1158/2159-8290.CD-22-1396
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© 2023 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under the Creative Commons Attribution- NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
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Grant ID
http://purl.org/au-research/grants/nhmrc/1071897
http://purl.org/au-research/grants/nhmrc/1182564
http://purl.org/au-research/grants/nhmrc/2021560
http://purl.org/au-research/grants/nhmrc/1148221
http://purl.org/au-research/grants/nhmrc/1123401
http://purl.org/au-research/grants/nhmrc/1098567
http://purl.org/au-research/grants/nhmrc/1117183
http://purl.org/au-research/grants/nhmrc/1194263
http://purl.org/au-research/grants/nhmrc/1182564
http://purl.org/au-research/grants/nhmrc/2021560
http://purl.org/au-research/grants/nhmrc/1148221
http://purl.org/au-research/grants/nhmrc/1123401
http://purl.org/au-research/grants/nhmrc/1098567
http://purl.org/au-research/grants/nhmrc/1117183
http://purl.org/au-research/grants/nhmrc/1194263