Key Points
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The use of tyrosine-kinase inhibitors (TKIs) in chronic myeloid leukaemia (CML) is one of the greatest single advances in the targeted treatment of cancer but, in most cases, TKI therapy suppresses but does not eliminate the leukaemia.
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Primitive CML cells are refractory to TKI therapy because of their acquisition of the complete physiology of stemness, which leads to relative quiescence and a protected reservoir for the breakpoint cluster region (BCR)–ABL (Abelson kinase) fusion. By contrast, progeny cells that persevere in the face of TKI therapy are resistant cells that might still be suppressed by second-generation TKIs or changes in doses of TKIs.
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At the onset, carcinogenesis in CML is driven by BCR–ABL and is completely dependent on this mutation — an example of oncogenic addiction. Over time, the effects of BCR–ABL on the behaviour of the cell disrupt cellular homeostasis and promote genomic instability, leading to a point at which CML may progress irrespective of BCR–ABL. Beyond this anaplastic threshold, TKI therapy becomes less reliable, indicating transition to advanced-stage CML.
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In advanced disease, it is genomic instability within the progeny cells that creates the disease phenotype, whereas the BCR–ABL fusion seems to simply persevere as a potential within the CML stem cell, implying that the fusion requires an increased rate of proliferation to exert its destabilizing effect. In fact, the relative quiescence might protect CML stem cells from TKI therapy, in so far as a minimum replicative index is required to actualize the pro-apoptotic effects of TKIs on the cell.
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There may be two distinct cell types capable of self renewal in different phases of CML: first, a long-term haematopoietic stem cell with the BCR–ABL mutation, or CML stem cell, which maintains the more indolent chronic-phase disease, providing proliferative and survival advantages and, second, a leukaemic granulocyte macrophage progenitor responsible for rapid cell expansion in advanced disease.
Abstract
Tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukaemia (CML) is the consummate success story for targeted therapy, yet relapse is a nearly inevitable consequence of cessation or interruption of therapy. Primitive TKI-refractory CML stem cells are the likely source of these relapses, as they provide sanctuary for the Philadelphia chromosome. In advanced disease, their progressively anaplastic progeny ultimately maintain CML independently of the CML haematopoietic stem cell (HSC). Interestingly, there are at least two distinct cell types capable of self-renewal in different phases of CML: first, a primitive HSC with BCR–ABL mutation, which maintains the more indolent chronic-phase disease and, second, a coexisting mutated progenitor cell which acquires stem cell characteristics responsible for rapid cell expansion in advanced disease.
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Acknowledgements
The authors apologize for omissions of citations as the manuscript limits restrict us from discussing and acknowledging some important works in this field. We would like to thank S. J. Morrison for assistance with generation of Figure 3; and J. P. Fossum for her tireless administrative assistance throughout the production of the manuscript.
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FURTHER INFORMATION
Glossary
- Karyotype analysis
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The preparation and study of chromosomes in dividing metaphase bone marrow cells to determine whether the normal human chromosomal complement (46) is present.
- SLAM markers
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The signalling lymphocyte attractant molecule (SLAM) family of markers are differentially expressed on haematopoietic cells, and certain combinations (for example, CD150+CD48−CD41−) reveal highly purified populations of primitive haematopoietic stem cells.
- Anaplastic threshold
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A point in the progression of CML at which the disease is no longer dependent on BCR–ABL and has the capacity to progress, if necessary, in the absence of the oncogene to which it was originally addicted
- Replicative index
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The relative rate at which cells divide, essentially interchangeable with the proliferative index. An HSC, for example, has a low replicative index, and a leukaemic blast has a comparably high index.
- Self-renewal signature
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A proposed set of genes which normally have a role in self-renewal in stem cells, and may be seen upregulated in malignant progeny cells.
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Savona, M., Talpaz, M. Getting to the stem of chronic myeloid leukaemia. Nat Rev Cancer 8, 341–350 (2008). https://doi.org/10.1038/nrc2368
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DOI: https://doi.org/10.1038/nrc2368
