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.
journal_name
Oncogenejournal_title
Oncogeneauthors
Sari IN,Yang YG,Wijaya YT,Jun N,Lee S,Kim KS,Bajaj J,Oehler VG,Kim SH,Choi SY,Park SH,Kim DW,Reya T,Han J,Kwon HYdoi
10.1038/s41388-020-01547-xsubject
Has Abstractpub_date
2021-01-01 00:00:00pages
603-617issue
3eissn
0950-9232issn
1476-5594pii
10.1038/s41388-020-01547-xjournal_volume
40pub_type
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