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Publication Abstract from PubMed

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.

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'Andrea RJ, Dick JE, Parker MW, Lopez AF Cancer Discov. 2023 Aug 4;13(8):1922-1947. doi: 10.1158/2159-8290.CD-22-1396. PMID:37191437^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.