Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/139756
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Type: | Journal article |
Title: | Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia |
Author: | 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. Dottore, M. Cheung Tung Shing, K.S. Thomas, D. Benard, B. Simpson, K.J. Schoof, E. Goodall, G.J. Begley, C.G. Ekert, P.G. Tvorogov, D. et al. |
Citation: | Cancer Discovery, 2023; 13(8):1922-1947 |
Publisher: | American Association for Cancer Research |
Issue Date: | 2023 |
ISSN: | 2159-8274 2159-8290 |
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 |
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. |
Keywords: | heterodimeric receptors stoichiometry biased signaling stem cells cytokines pleiotropy stemness leukemia receptor oligomerization |
Description: | Published first May 16, 2023 |
Rights: | © 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. |
DOI: | 10.1158/2159-8290.CD-22-1396 |
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 |
Published version: | http://dx.doi.org/10.1158/2159-8290.cd-22-1396 |
Appears in Collections: | Medicine publications |
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File | Description | Size | Format | |
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hdl_139756.pdf | Published version | 18.44 MB | Adobe PDF | View/Open |
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