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The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

Abstract

For two decades, leukaemia stem cells (LSCs) in chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) have been advanced paradigms for the cancer stem cell field. In CML, the acquisition of the fusion tyrosine kinase BCR–ABL1 in a haematopoietic stem cell drives its transformation to become a LSC. In AML, LSCs can arise from multiple cell types through the activity of a number of oncogenic drivers and pre-leukaemic events, adding further layers of context and genetic and cellular heterogeneity to AML LSCs not observed in most cases of CML. Furthermore, LSCs from both AML and CML can be refractory to standard-of-care therapies and persist in patients, diversify clonally and serve as reservoirs to drive relapse, recurrence or progression to more aggressive forms. Despite these complexities, LSCs in both diseases share biological features, making them distinct from other CML or AML progenitor cells and from normal haematopoietic stem cells. These features may represent Achilles’ heels against which novel therapies can be developed. Here, we review many of the similarities and differences that exist between LSCs in CML and AML and examine the therapeutic strategies that could be used to eradicate them.

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Fig. 1: Scientific and clinical milestones relevant to CML and AML LSCs.
Fig. 2: The evolving LSC.
Fig. 3: The epigenetic and metabolic axis in LSCs.

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Acknowledgements

D.V. and M.C. are jointly funded by Bloodwise (Ref. 14033) and the Stand Up To Cancer campaign for Cancer Research UK (Ref. C55731/A24896). G.V.H. is funded by the Kay Kendall Research Fund (Ref. KKL1069), the Howat Foundation and Bloodwise (Ref. 18006).

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D.V., G.V.H. and M.C. researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to David Vetrie or Mhairi Copland.

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The authors declare no competing interests.

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Dedication: The authors dedicate this Review to our absent colleague Tessa Laurie Holyoake, whose untimely passing in 2017 cut short the life of a brilliant clinician and scientist. Her discovery of the quiescent CML LSC in 1999, her dedication to the preclinical study of LSCs in the years that followed and her commitment to cure CML, paved the way for many of the scientific discoveries discussed here.

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Related links

Cancer Research UK: https://www.cancerresearchuk.org/

ClinicalTrials.gov: https://clinicaltrials.gov/

Surveillance, Epidemiology, and End Results Program: https://seer.cancer.gov/

Glossary

Philadelphia chromosome

(Ph). The chromosomal abnormality characteristic of CML cells that arises from a reciprocal translocation between chromosomes 9 and 22.

Relative survival

The percentage survival of individuals with leukaemia after taking into account death rates of individuals without leukaemia.

Immunophenotype

A population of cells characterized by markers expressed on the cell surface as determined by flow cytometry.

Chimerism

The relative proportions of human to mouse cells that result when human cells are engrafted into the bone marrow of immunocompromised mice.

Clonal haematopoiesis of indeterminant potential

(CHIP). A process that occurs in some older individuals whereby DNA mutations in haematopoietic stem cells result in the accumulation of clonally expanded populations of haematopoietic cells.

Haemangioblasts

Multipotent precursor cells that can give rise to both haematopoietic stem cells and enthothelial cells.

Oxidative phosphorylation

(OXPHOS). The mitochondrial process in which electrons are transferred from NADH or FADH2 to oxygen (O2) through a series of carriers and protein complexes to produce ATP from ADP and phosphate.

BH3 mimetic

One of a class of compounds that bind to a hydrophobic groove found in antiapoptotic proteins and prevents them from binding to the BH3 domain of the BCL-2 family of proteins.

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Vetrie, D., Helgason, G.V. & Copland, M. The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML. Nat Rev Cancer 20, 158–173 (2020). https://doi.org/10.1038/s41568-019-0230-9

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