American Association for Cancer Research
Browse

Supplementary Table S2 from Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia

Download (139.15 kB)
journal contribution
posted on 2023-08-04, 08:40 authored by 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, Angel F. Lopez

Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.

Funding

National Health and Medical Research Council (NHMRC)

Cancer Council South Australia (Cancer Council SA)

Cancer Council Victoria

Cure Cancer Australia Foundation (CCAF)

Australian Cancer Research Foundation (ACRF)

Leukaemia Foundation (Leukaemia Foundation)

Princess Margaret Cancer Foundation (PMCF)

Ontario Institute for Cancer Research (OICR)

Canadian Institutes of Health Research (IRSC)

International Development Research Centre (IDRC)

Canadian Cancer Society (CCS)

Terry Fox Research Institute (TFRI)

Canada First Research Excellence Fund (CFREF)

Canada Research Chairs (Chaires de recherche du Canada)

History

ARTICLE 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. Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies.This article is highlighted in the In This Issue feature, p. 1749

Usage metrics

    Cancer Discovery

    Categories

    Keywords

    cancer

    Licence

    CC BY

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC