Poster Presentation 37th Lorne Cancer Conference 2025

Transcriptional regulation of acute myeloid leukaemia stem cells by the IL-3 receptor (#181)

Nora W. Liu 1 2 , Winnie L. Kan 3 , Saumya E. Samaraweera 4 , Richard J. D’Andrea 4 , Michael W. Parker 5 6 7 , Angel F. Lopez 3 8 , Luciano G. Martelotto 1 2 , Jose M. Polo 1 2
  1. Cancer Epigenetics Program, The South Australian immunoGENomics Cancer Institute, The University Of Adelaide, Adelaide, South Australia, Australia
  2. Adelaide Centre for Epigenetics, School of Biomedicine, The University Of Adelaide, Adelaide, South Australia, Australia
  3. Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia
  4. Acute Leukaemia Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia
  5. Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
  6. Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Victoria, Australia
  7. Australian Cancer Research Foundation Rational Drug Discovery Centre, St Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
  8. Department of Medicine, The University of Adelaide, Adelaide, SA, Australia

Acute myeloid leukemia (AML) is a lethal blood cancer driven by leukemia stem cells (LSCs), a rare population capable of initiating, sustaining, and causing relapse in AML. Although up to 70% of patients achieve initial remission, relapse is common, underscoring the need to better understand the LSC stemness regulation and AML recurrence. Previous studies have shown that the IL3Rα subunit is selectively upregulated on LSCs and myeloid blasts in 90% of AML patients, correlating with high blast counts and poor prognosis, suggesting a role in AML pathogenesis. However, our recent findings reveal that the IL-3 receptor's stoichiometry, specifically the ratio of IL3Rα to βc subunits, is the key determinant in LSC function (Ref 1.)

We found that LSC stemness is intricately regulated by the assembly of the IL-3 receptor (IL3R) as either hexamers or dodecamers (Ref 1). High IL3Rα/βc ratios in LSCs favor hexamer formation, while low ratios promote dodecamer assembly. Using mouse and human stem and progenitor cell models and primary AML patient samples, we demonstrated that activation of the hexameric IL-3 receptor in LSCs triggers a transcriptional stemness program. Our current focus is on dissecting LSC heterogeneity and elucidating how IL3R stoichiometry regulates AML stem cell programs. Through profiling primary AML patients with high or low IL3Rα/βc ratios stimulated with IL-3 via single-cell RNA sequencing, we are now working to directly link the distinct IL3R hexamer vs dodecamer transcriptional programs to IL3R α/βc ratio in various cell subsets.

This study will elucidate the heterogeneity within the LSC population and build cell differentiation trajectories to uncover the divergent differentiation potentials of high- vs low- IL3Rα/βc ratio LSCs. Data will be presented demonstrating the enrichment of stemness and IL3R hexamer transcriptional programs in high vs low IL3Rα/βc ratio cell populations. Currently, we are constructing gene regulatory networks across distinct cell types to identify signalling pathways activated by the different IL3R assembly forms and key downstream transcription factors mediating distinct stemness and differentiation programs. Ultimately, our goal is to identify therapeutic targets that can reprogram LSC fate and establish patient-derived hexamer signatures for more accurate prognosis and relapse prediction.

  1. Kan et al., Cancer Discovery 2023, 13: 1922 -1947.