Oncogene Addiction in Chronic Myeloid Leukaemia

Abstract

Oncogene addiction is the dependence seen in some types of cancer cells on the presence or activity of an oncogene. Chronic myeloid leukaemia (CML) is driven by the BCR‐ABL1 oncogene. CML has become a paradigm for targeted therapies, as the disease is effectively managed in most patients by BCR‐ABL1 inhibitors. Although the symptom‐causing leukaemic progenitor cells depend on the kinase activity of BCR‐ABL1 for survival, the more primitive leukaemia stem cells (LSCs) responsible for disease maintenance and relapse are not dependent on the BCR‐ABL1 oncogene and lie dormant in the bone marrow of patients during treatment. The advances in knowledge achieved through the study of CML LSCs indicate that cancer stem cells (CSCs), which underlie many different cancers, may not display oncogene addiction in the classical sense. This provides yet another obstacle to the efforts to cure cancers using targeted therapies. To eradicate these CSCs and discover ways to truly cure CML and other CSC‐driven cancers, we must investigate them for their unique dependencies.

Key Concepts

  • Oncogene addiction refers to the dependence of some types of cancer cells on the presence or activity of an oncogene.
  • Cancer researchers are working to identify sources of oncogene addiction, as they represent attractive therapeutic targets.
  • Chronic myeloid leukaemia progenitor cells are dependent on BCR‐ABL1 oncogenic kinase activity for their survival.
  • Targeting the ‘addictive’ BCR‐ABL1 oncoprotein has proved to be a successful therapeutic strategy for managing chronic myeloid leukaemia.
  • Some cancers are maintained by self‐renewing multipotent cancer stem cells.
  • Cancer stem cells have demonstrated the ability to escape oncogene addiction, for example, in chronic myeloid leukaemia.
  • Activation of alternative survival pathways may protect cancer stem cells from therapeutic targeting of proteins encoded by oncogenes.
  • Combining high‐throughput and single‐cell technologies could be a powerful strategy to investigate oncogene dependencies of cancer stem cells.

Keywords: BCR‐ABL1; cancer; cancer stem cell; chronic myeloid leukaemia; fusion oncogene; leukaemia; oncogene; oncogene addiction; targeted therapy; tyrosine kinase inhibitors

Figure 1. The identification of the reciprocal translocation t(9;22) by Rowley in 1973 opened avenues in CML (chronic myeloid leukaemia) research. (a) Idiotype of the t(9q;22q) translocation that leads to formation of the BCR‐ABL1 fusion oncogene (Apperley, ). (b) Giemsa stain showing the chromosomes produced by the t(9q;22q) translocation (Rowley, ). Reprinted by permission from Macmillan Publishers Ltd: Nature (Rowley, J. D. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. 243: 290–293), copyright (1973). (c) Representation of the catalytic pocket of the tyrosine kinase domain of BCR‐ABL1 with imatinib in situ in the ATP‐binding loop (Apperley, ). (a,c) Adapted from Lancet 385, Chronic myeloid leukaemia 1447–1459, copyright (2015), with permission from Elsevier. (d) Schematic representation of the BCR‐ABL1 protein domains: oligomerisation domain (OLI), serine/threonine kinase domain (S/TK), domain homologous to the human Dbl and yeast Cdc24 proteins (DH), Src‐homology domains 3/2 (SH3/SH2), tyrosine kinase domain (TK), nuclear translocalisation signal (NTS), DNA binding domain (DB) and actin‐binding motif (AB). OLI and TK are instrumental in the oncogenic capacity of BCR‐ABL1. Green: domains encoded by the BCR gene. Orange: domains encoded by the ABL1 gene. (e) Common mutations in the tyrosine kinase domain of BCR‐ABL1 that can precipitate resistance to TKIs (Zabriskie et al., ). Reprinted from Cancer Cell, 26, M.S. Zabriskie, C.A. Eide, S.K. Tantravahi, N.A. Vellore, J. Estrada, F.E. Nicolini, H.J. Khoury, R.A. Larson, M. Konopleva, J.E. Cortes, BCR‐ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome‐positive leukemia, 428–442., Copyright (2014), with permission from Elsevier.
Figure 2. Simplified representation of some of the BCR‐ABL1‐dependent signalling pathways activated in CML, which underlie disease phenotype by enhancing proliferation and survival of leukaemic cells. The BCR‐ABL1 fusion protein forms homotetramers via the oligomerisation domain (OLI) of BCR, triggering transactivation through autophosphorylation of the tyrosine kinase domain (TK) of ABL1 (single monomer shown for clarity). This activates ABL1 kinase activity, enabling phosphorylation of key signalling proteins. Adaptor proteins (blue), transcription factors (red), kinases (purple) and mediators of apoptosis (pink) involved in these pathways are shown.
Figure 3. Timeline of therapeutic strategies for treatment of CML.
Figure 4. Network analysis of proteome‐wide differences suggests that CML cells display an altered dependency on c‐MYC and p53 compared to normal cells. Reproduced with permission from Abraham et al. 2016 © Nature Publishing Group.
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Further Reading

Choi PS, Li Y and Felsher DW (2014) Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance. Proceedings of the National Academy of Sciences of the United States of America 111: E3316–E3324.

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Jackson, Lorna, Gómez‐Castañeda, Eduardo, Jørgensen, Heather G, Hopcroft, Lisa EM, Rogers, Simon, Holyoake, Tessa L, and Huang, Xu(Nov 2017) Oncogene Addiction in Chronic Myeloid Leukaemia. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024464]