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AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth

Oncogene volume 40, pages 603–617 (2021)Cite this article

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Abstract

Polyamines are critical elements in mammals, but it remains unknown whether adenosyl methionine decarboxylase (AMD1), a rate-limiting enzyme in polyamine synthesis, is required for myeloid leukemia. Here, we found that leukemic stem cells (LSCs) were highly differentiated, and leukemia progression was severely impaired in the absence of AMD1 in vivo. AMD1 was highly upregulated as chronic myeloid leukemia (CML) progressed from the chronic phase to the blast crisis phase, and was associated with the poor prognosis of CML patients. In addition, the pharmacological inhibition of AMD1 by AO476 treatment resulted in a robust reduction of the progression of leukemic cells both in vitro and in vivo. Mechanistically, AMD1 depletion induced loss of mitochondrial membrane potential and accumulation of reactive oxygen species (ROS), resulting in the differentiation of LSCs via oxidative stress and aberrant activation of unfolded protein response (UPR) pathway, which was partially rescued by the addition of polyamine. These results indicate that AMD1 is an essential element in the progression of myeloid leukemia and could be an attractive target for the treatment of the disease.

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Fig. 1: Amd1 is required for the growth and maintenance of LSCs.
Fig. 2: Spermidine addition partially rescues the defects caused by AMD1 depletion.
Fig. 3: Amd1 is indispensable in the progression of bcCML in vivo.
Fig. 4: Higher levels of reactive oxygen species (ROS) in the absence of Amd1 partly contribute to the lineage differentiation of LSCs.
Fig. 5: LSCs differentiation induced by ROS was reduced by spermidine addition.
Fig. 6: LSCs differentiation in the absence of Amd1 is mediated by ROS-induced Atf3 or Atf4.
Fig. 7: AMD1 is associated with a poor prognosis of CML and required for growth of myeloid leukemia.
Fig. 8: AO476 inhibits proliferation and engraftment of myeloid leukemic cells in vitro and in vivo.

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Data availability

All data generated during this study are included either in article or in the additional files. RNA-seq data are uploaded to GEO database.

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Acknowledgements

We would also like to thank Warren Pear for the BCR-ABL construct, Gary Gilliland for the NUP98-HOXA9 construct, and Sen Liu for the personal communication regarding AO476.

Funding:

This work was supported by the National Research Foundation of Korea (NRF-2020R1A2C1003791 and NRF-2019R1A5A8083404), the grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHID), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C1647) and Global Research Development Center (NRF-2016K1A4A3914725).

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  1. These authors contributed equally: Ita Novita Sari, Ying-Gui Yang

Authors and Affiliations

  1. Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, Republic of Korea

    Ita Novita Sari, Ying-Gui Yang, Yoseph Toni Wijaya, Nayoung Jun, Sanghyun Lee, Kwang Seock Kim, Jaeseok Han & Hyog Young Kwon

  2. Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China

    Ying-Gui Yang

  3. Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA

    Jeevisha Bajaj & Tannishtha Reya

  4. Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA

    Jeevisha Bajaj & Tannishtha Reya

  5. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Vivian G. Oehler

  6. Catholic Leukemia Research Institute, The Catholic University of Korea, Seoul, Republic of Korea

    Soo-Hyun Kim, Soo-Young Choi, Sa-Hee Park & Dong-Wook Kim

  7. Department of Hematology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea

    Dong-Wook Kim

  8. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA

    Tannishtha Reya

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Contributions

INS, YY, NJ, SL, and JB planned, designed and performed the majority of experiments and helped write the manuscript. VGO, SHK, SYC, SHP, DWK provided primary leukemia patient samples and patients information. TR and JH helped design the project. HYK planned and guided the project and wrote the manuscript.

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Correspondence to Hyog Young Kwon.

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Sari, I.N., Yang, YG., Wijaya, Y.T. et al. AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth. Oncogene 40, 603–617 (2021). https://doi.org/10.1038/s41388-020-01547-x

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