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Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia

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dc.contributor.authorKan, W.L.
dc.contributor.authorDhagat, U.
dc.contributor.authorHercus, T.R.
dc.contributor.authorKaufmann, K.B.
dc.contributor.authorNero, T.L.
dc.contributor.authorZeng, A.G.X.
dc.contributor.authorToubia, J.
dc.contributor.authorBarry, E.F.
dc.contributor.authorBroughton, S.E.
dc.contributor.authorGomez, G.A.
dc.contributor.authorDottore, M.
dc.contributor.authorCheung Tung Shing, K.S.
dc.contributor.authorThomas, D.
dc.contributor.authorBenard, B.
dc.contributor.authorSimpson, K.J.
dc.contributor.authorSchoof, E.
dc.contributor.authorGoodall, G.J.
dc.contributor.authorBegley, C.G.
dc.contributor.authorEkert, P.G.
dc.contributor.authorTvorogov, D.
dc.contributor.authoret al.
dc.date.issued2023
dc.descriptionPublished first May 16, 2023 Data source: Supplementary data, https://doi.org/10.1158/2159-8290.CD-22-1396
dc.description.abstractLeukemia 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.
dc.description.statementofresponsibilityWinnie 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
dc.identifier.citationCancer Discovery, 2023; 13(8):1922-1947
dc.identifier.doi10.1158/2159-8290.CD-22-1396
dc.identifier.issn2159-8274
dc.identifier.issn2159-8290
dc.identifier.orcidBarry, E.F. [0000-0003-2742-5650]
dc.identifier.orcidGoodall, G.J. [0000-0003-1294-0692]
dc.identifier.orcidLopez, A. [0000-0001-7430-0135]
dc.identifier.urihttps://hdl.handle.net/2440/139756
dc.language.isoen
dc.publisherAmerican Association for Cancer Research
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1071897
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1182564
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2021560
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1148221
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1123401
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1098567
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1117183
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1194263
dc.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.
dc.source.urihttps://doi.org/10.1158/2159-8290.CD-22-1396
dc.subjectheterodimeric receptors
dc.subjectstoichiometry
dc.subjectbiased signaling
dc.subjectstem cells
dc.subjectcytokines
dc.subjectpleiotropy
dc.subjectstemness
dc.subjectleukemia
dc.subjectreceptor oligomerization
dc.subject.meshHumans
dc.subject.meshReceptors, Cytokine
dc.subject.meshSignal Transduction
dc.subject.meshCell Proliferation
dc.subject.meshPhosphorylation
dc.subject.meshNeoplastic Stem Cells
dc.subject.meshLeukemia, Myeloid, Acute
dc.titleDistinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
dc.typeJournal article
pubs.publication-statusPublished

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