Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia

Kan, WL; Dhagat, U; Kaufmann, KB; Hercus, TR; Nero, TL; Zeng, AGX; Toubia, J; Barry, EF; Broughton, SE; Gomez, GA; Benard, BA; Dottore, M; Cheung Tung Shing, KS; Boutzen, H; Samaraweera, SE; Simpson, KJ; Jin, L; Goodall, GJ; Begley, CG; Thomas, D; Ekert, PG; Tvorogov, D; D&#39;Andrea, RJ; Dick, JE; Parker, MW; Lopez, AF

Author(s): Kan, WL; Dhagat, U; Kaufmann, KB; Hercus, TR; Nero, TL; Zeng, AGX; Toubia, J; Barry, EF; Broughton, SE; Gomez, GA; Benard, BA; Dottore, M; Cheung Tung Shing, KS; Boutzen, H; Samaraweera, SE; Simpson, KJ; Jin, L; Goodall, GJ; Begley, CG; Thomas, D; Ekert, PG; Tvorogov, D; D'Andrea, RJ; Dick, JE; Parker, MW; Lopez, AF;
Details: Publication Year 2023-08-04,Volume 13,Issue #8,Page 1922-1947
Journal Title: Cancer Discovery
Publication Type: Research 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 IL3Ralpha/betac receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Ralpha/betac ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Ralpha/betac 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. 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.
Publisher: American Association for Cancer Research
Keywords: Humans; *Receptors, Cytokine/therapeutic use; *Leukemia, Myeloid, Acute/genetics/drug therapy; Phosphorylation; Signal Transduction; Cell Proliferation; Neoplastic Stem Cells
Department(s): Laboratory Research
PubMed ID: 37191437
Publisher's Version: https://doi.org/10.1158/2159-8290.CD-22-1396
Open Access at Publisher's Site: https://doi.org/10.1158/2159-8290.Cd-22-1396
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-10-24 12:16:55

Last Modified: 2023-10-24 12:19:00