AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth
Authors: Sa-Hee Park
Hyog Young Kwon
Jeevisha Bajaj
Tannishtha Reya
Ita Novita Sari
Jaeseok Han
Dong-Wook Kim
Kwang Seock Kim
Sanghyun Lee
Ying-Gui Yang
Soo-Hyun Kim
Vivian G Oehler
Yoseph Toni Wijaya
Nayoung Jun
Soo-Young Choi
Journal: Oncogene (2021)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Polyamines; Adenosyl methionine decarboxylase (AMD1); Myeloid leukemia; Leukemic stem cells (LSCs); Chronic myeloid leukemia (CML)
Affiliations: Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, Republic of Korea., Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China., Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA., Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA., Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Catholic Leukemia Research Institute, The Catholic University of Korea, Seoul, Republic of Korea., Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea., Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA., Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, Republic of Korea. .

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. 

Retracted: No

PubPeer comments:
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 Answer to Comment 1: Upon magnification and inversion it is evident these three are different images. Notches in smar1 are not present inu00a0H3K9me3.u00a0u00a0Also the curvature of p53 is more in the middle lane compared to the other two ![file] Answer to Comment 2: Thank you for pointing this. We found a copy of the preparatory file used for assembly. We apologize that during assembly the image has been invert pasted. However, the results remain same and do not change. ![file] - Samit Chattopadhyay ,