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New routes to eradicating chronic myelogenous leukemia stem cells by targeting metabolism

Abstract

Chronic myelogenous leukemia (CML) stem cells are the cellular source of the vast majority of mature CML cells and responsible for relapse of CML disease post-tyrosine kinase inhibitor (TKI) therapy. Although mature CML cells, whose active division is driven by BCR-ABL1 oncogene-dependent signaling, are reduced by TKI therapy, CML stem cells are resistant because they become quiescent via a heretofore elusive mechanism that is independent of oncogene signaling. Recent advances in highly sensitive metabolomics analyses, however, have unveiled new metabolic pathways that are essential for the survival of CML stem cells. With respect to glucose metabolism, CML stem cells elevate anaplerosis to sustain the TCA cycle. Blast crisis (BC)-CML stem cells increase their branched-chained amino acid (BCAA) metabolism. Recently, we showed that CML stem cell quiescence in vivo is regulated by lysophospholipid metabolism that is specific to these cells, namely cooperation between the stemness factors FOXO and β-catenin. These findings reveal biologically significant links between CML stemness and novel metabolic mechanisms. In this review, I describe these links in the contexts of glucose, amino acid, and lipid metabolism, and speculate on how innovative therapeutics might be designed to eradicate CML stem cells in vivo and overcome disease relapse post-TKI therapy.

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Acknowledgements

The author was supported by a grant-in-aid for Scientific Research (B) (KAKENHI Grant Numbers 20H0351700) from the Ministry of Education, Culture, Sports, Science and Technology, Japan; and by the Takashi Ogimura Special Award from the Friends of Leukemia Research Fund, Japan.

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Correspondence to Kazuhito Naka.

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The author was supported by a grant-in-aid from Carna Biosciences Inc., Japan.

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Naka, K. New routes to eradicating chronic myelogenous leukemia stem cells by targeting metabolism. Int J Hematol 113, 648–655 (2021). https://doi.org/10.1007/s12185-021-03112-y

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  • DOI: https://doi.org/10.1007/s12185-021-03112-y

Keywords

  • CML stemness
  • Anaplerosis
  • BCAA
  • Lysophospholipid