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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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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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.
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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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 (2020). https://doi.org/10.1038/s41388-020-01547-x