AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth
- 17 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (3), 603-617
- https://doi.org/10.1038/s41388-020-01547-x
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.Keywords
This publication has 49 references indexed in Scilit:
- The mechanisms by which polyamines accelerate tumor spreadJournal of Experimental & Clinical Cancer Research, 2011
- Mammalian polyamine metabolism and functionIUBMB Life, 2009
- Targeting polyamine metabolism and function in cancer and other hyperproliferative diseasesNature Reviews Drug Discovery, 2007
- Biological significance of dietary polyaminesNutrition, 2007
- Emerging Concepts in Targeting the Polyamine Metabolic Pathway in Epithelial Cancer Chemoprevention and ChemotherapyThe Journal of Biochemistry, 2006
- Polyamines and cancer: old molecules, new understandingNature Reviews Cancer, 2004
- Polyamines as clinical laboratory toolsClinica Chimica Acta; International Journal of Clinical Chemistry, 2004
- Polyamine metabolism revisitedEuropean Journal of Gastroenterology & Hepatology, 2001
- Polyamine transport in mammalian cells. An updateThe International Journal of Biochemistry & Cell Biology, 1996
- Polyamines as Targets for Therapeutic InterventionAnnual Review of Pharmacology and Toxicology, 1995