Polyamine depletion limits progression of acute leukaemia

Weiman Gao^{1

2}, Mawar Karsa^{1

2}, Lin Xiao^{1

2}, Dayna Spurling¹, Ayu Karsa¹, Emma Ronca¹, Angelika Bongers¹, Xinyi Guo¹, Chelsea Mayoh^{1

2}, Mujahid Azfar³, Steven H L Verhelst⁴, Katsunori Tanaka^{5

6}, Laurence C Cheung^{7

8

9}, Rishi S Kotecha^{7

8

10

11}, Richard B Lock^{1

2}, Mark R Burns¹², Peter Vangheluwe³, Murray D Norris^{1

2}, Michelle Haber^{1

2}, Klaartje Somers^{1

2}

Affiliations

¹ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, New South Wales, Australia.
² School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer research, UNSW Sydney, Sydney, New South Wales, Australia.
³ Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
⁴ Laboratory of Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
⁵ Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, Tokyo, Japan.
⁶ Biofunctional Synthetic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, Saitama, Japan.
⁷ Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, Western Australia, Australia.
⁸ Curtin Medical School, Curtin University, Perth, Western Australia, Australia.
⁹ Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
¹⁰ Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children's Hospital, Perth, Western Australia, Australia.
¹¹ Division of Paediatrics, School of Medicine, University of Western Australia, Perth, Western Australia, Australia.
¹² Aminex Therapeutics, Aminex Therapeutics Inc., Kirkland, Washington, DC, USA.

PMID: 39985426
DOI: 10.1002/ijc.35362

Polyamine depletion limits progression of acute leukaemia

Weiman Gao et al. Int J Cancer. 2025.

. 2025 Jun 15;156(12):2360-2376.

doi: 10.1002/ijc.35362. Epub 2025 Feb 22.

Authors

Affiliations

¹ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, New South Wales, Australia.
² School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer research, UNSW Sydney, Sydney, New South Wales, Australia.
³ Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
⁴ Laboratory of Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
⁵ Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, Tokyo, Japan.
⁶ Biofunctional Synthetic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, Saitama, Japan.
⁷ Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, Western Australia, Australia.
⁸ Curtin Medical School, Curtin University, Perth, Western Australia, Australia.
⁹ Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
¹⁰ Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children's Hospital, Perth, Western Australia, Australia.
¹¹ Division of Paediatrics, School of Medicine, University of Western Australia, Perth, Western Australia, Australia.
¹² Aminex Therapeutics, Aminex Therapeutics Inc., Kirkland, Washington, DC, USA.

PMID: 39985426
DOI: 10.1002/ijc.35362

Abstract

Cancer cells are addicted to polyamines, polycations essential for cellular function. While dual targeting of cellular polyamine biosynthesis and polyamine uptake is under clinical investigation in solid cancers, preclinical and clinical studies into its potential in haematological malignancies are lacking. Here we investigated the preclinical efficacy of polyamine depletion in acute leukaemia. The polyamine biosynthesis inhibitor difluoromethylornithine (DFMO) inhibited growth of a molecularly diverse panel of acute leukaemia cell lines, while non-malignant cells were unaffected. Responsiveness to DFMO was linked to decreased levels of its molecular target, the rate-limiting polyamine biosynthesis enzyme ODC1, and of the polyamine transporters ATP13A2 and ATP13A3. DFMO increased polyamine uptake and upregulated expression of polyamine transporters in acute leukaemia cells, a compensatory effect abolished by treatment with the polyamine transport inhibitor AMXT 1501. This drug, currently in a phase 1 clinical trial in solid tumours in combination with DFMO, potentiated the inhibitory effects of DFMO, and their combination synergistically inhibited the growth of acute leukaemia cell lines by inducing apoptosis. DFMO and AMXT 1501 limited disease progression in highly aggressive xenograft models of infant KMT2A-rearranged leukaemia, even when treatment was initiated at high disease burden. Increased expression of c-MYC was associated with enhanced sensitivity to the combination of DFMO and AMXT 1501, suggesting this oncoprotein as a potential predictive marker of response to the drug combination. In conclusion, targeting polyamine biosynthesis and polyamine uptake limits disease progression in models of acute leukaemia, supporting further preclinical and clinical investigation into this approach for acute leukaemia.

Keywords: DFMO; acute leukaemia; polyamine depletion; polyamine transport; polyamines.

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References

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Polyamine depletion limits progression of acute leukaemia

Affiliations

Polyamine depletion limits progression of acute leukaemia

Authors

Affiliations

Abstract

References

REFERENCES

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials