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Chronic myeloid leukaemia as a model of disease evolution in human cancer

Nature Reviews Cancer volume 7, pages 441–453 (2007)Cite this article

Key Points

  • Chronic myeloid leukaemia (CML) can be considered, for some aspects, a model for malignant tumours that evolve through a multi-step pathogenetic process. In its natural history, CML is usually diagnosed in chronic phase (CP) and then progresses through an accelerated phase to a nearly invariably fatal blast crisis (BC).

  • The mechanisms of transformation to BC are varied and not entirely understood. So far the best characterized include differentiation arrest, genomic instability, telomere shortening and loss of tumour-suppressor functions.

  • The differentiation arrest of the transformed BC clone is caused by the suppression of translation of the transcription factor CEBPα induced by the BCR-ABL oncoprotein in CML cells, through increased stability of the heterogenous nuclear ribonucleoprotein E2 translational regulator.

  • The increased genomic instability in CML cells is the result of their reduced capacity to survey the genome for DNA damage and to correctly repair DNA lesions, which leads to the accumulation of deleterious mutations in genes that are essential for maintaining normal cell physiology and maturation.

  • The impairment of several tumour-suppressor genes has been variably associated with BC of CML, including TP53, retinoblastoma 1, CDKN2A and others. Protein phosphatase 2a (PP2A) has an important role, as it is inhibited by BCR-ABL in BC cells by the post-transcriptional upregulation of SET, a phosphoprotein that is frequently overexpressed in other leukaemias and solid tumours.

  • Recent expression profiling of cells from different stages of CML has uncovered several genes that are differentially expressed in BC and in extremely aggressive forms of the disease. These are likely to be associated with the kinetics of blastic transformation.

  • It is envisaged that the identification of the most pathologically relevant genetic lesions for the development of BC will allow the early diagnosis of impending disease progression and the design of new treatment strategies to halt this process. Such an approach can become the paradigm for therapy decision making in other types of cancer.

Abstract

Chronic myeloid leukaemia (CML) can be considered as a paradigm for neoplasias that evolve through a multi-step process. CML is also one of the best examples of a disease that can be targeted by molecular therapy; however, the success of new 'designer drugs' is largely restricted to the chronic phase of the disease. If not cured at this stage, CML invariably progresses and transforms into an acute-type leukaemia undergoing a 'blast crisis'. The causes of this transformation are still poorly understood. What mechanisms underlie this progression, and are they shared by other common cancers?

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Figure 1: Disease progression in chronic myeloid leukaemia.
Figure 2: BCR-ABL contributes to differentiation arrest through interference with the translation of the transcription factor CEBPα.
Figure 3: BCR-ABL and genomic instability.
Figure 4: BCR-ABL inactivates the tumour suppressor protein phosphatase 2A (PP2A).

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Acknowledgements

We are very grateful to J. M. Goldman for kindly reviewing and commenting on this manuscript.

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Authors and Affiliations

  1. Department of Haematology, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Junia V. Melo & David J. Barnes

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  1. Junia V. Melo
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Correspondence to Junia V. Melo.

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DATABASES

National Cancer Institute

CML

FURTHER INFORMATION

Imperial College — Molecular biology of CML group

Glossary

Chronic phase

The initial stage of CML, in which most patients are diagnosed. It usually has an insidious onset, and the main clinical findings include enlarged spleen, fatigue and weight loss. The peripheral blood shows leukocytosis (approximately 150 ×109/L white blood cells (WBCs)), predominantly owing to neutrophils in different stages of maturation, as well as basophilia and eosinophilia. Blasts usually represent <2% of the WBCs. The platelet count is normal or increased.

Accelerated phase

An intermediate stage of CML evolution, when the disease starts to become refractory to therapy. It is characterized by an increase in spleen size and in total WBCs, blasts comprising 10–19% of the WBCs, >20% circulating basophils, persistent thrombocytopenia and/or the appearance of new clonal cytogenetic abnormalities.

Blast crisis

The final stage of CML, which may or may not be preceded by an 'accelerated phase'. Patients experience worsened performance status, and symptoms related to thrombocytopenia, anaemia and increased spleen enlargement. The WHO (World Health Organization) criteria for the diagnosis of blast crisis include: blasts in excess of 20% in the peripheral blood or bone marrow; and/or extramedullary blast proliferation; and/or large foci or clusters of blasts in bone marrow histological sections.

Mutator phenotype

A mutator phenotype arises owing to mutations in genes that are crucial for maintaining genomic stability.

Telomere

The termini of eukaryotic chromosomes that function to prevent the loss of genetic material. Human telomeres consist of tandem repeats of the DNA sequence TTAGGG. Telomerase is a ribonucleoprotein, required for the maintenance of telomeres, consisting of an RNA template and a catalytic subunit (TERT in humans). Whereas human stem cells express telomerase and retain intact telomeres, most somatic cells do not, and consequently have telomeres that become shorter with successive cell divisions.

STAT5

A transcription factor that is activated by multiple haematopoietic cytokines. In cell lines, BCR-ABL was shown to catalyse the phosphorylation of tyrosine residues on STAT5, leading to its constitutive activation. STAT5 promotes cell survival and proliferation by transactivating anti-apoptotic genes (BCL-XL) and genes associated with cell-cycle progression (cyclin D1).

CD34

A cell-surface protein expressed by haematopoietic stem cells, haematopoietic progenitor cells and endothelial cells, which is used as a marker to isolate human haematopoietic progenitor cells.

Ataxia telangiectasia

A recessive disorder caused by inactivating mutations in the ATM gene and characterized by X-ray hypersensitivity, genomic instability and a predisposition to both solid tumours and haematological malignancies.

Intra-S-phase cell-cycle checkpoint

Normally, the activated intra-S-phase checkpoint delays the cell cycle, providing additional time for DNA repair, or for initiating apoptosis, if the damage is irreparable.

BRCA1-associated genome surveillance complex

(BASC). This DNA damage repair complex includes repair proteins and tumour suppressors (MSH2, MSH6, MLH1, ATM and BLM) as well as the RAD50–MRE11–NBS1 complex.

Mononuclear cells

The fraction of leukocytes consisting of lymphocytes, monocytes and immature granulocytes (blasts, promyelocytes, myelocytes and metamyelocytes) that is obtained by density centrifugation of the peripheral blood for exclusion of the polymorphonuclear cells (that is, band and segmented granulocytes).

Xeroderma pigmentosum

(XP). An inherited genetic disorder characterized by an inability to repair DNA damage resulting from exposure to UV light. Before the discovery of the mutated genes that cause this condition, patients were classified into 7 complementation groups (XPA, XPB, XPC, XPD, XPE, XPF and XPG).

Depurination

A form of spontaneous DNA damage in which purines (adenine or guanine) are lost from a DNA strand resulting in the formation of an 'abasic' site.

Deamination

Another form of spontaneous DNA damage in which amino groups are lost from the bases adenine, guanine, cytosine or 5-methylcytosine, converting them to their miscoding equivalents of hypoxanthine, xanthine, uracil and thymine, respectively.

Rubinstein–Taybi malformation syndrome

An inherited condition characterized by short stature, broad thumbs and first toes, unusual facial features and moderate to severe mental retardation. Individuals with this condition are predisposed to developing non-malignant and malignant tumours, as well as having an increased risk of developing leukaemia or lymphoma. The condition is caused by inactivating autosomal dominant mutations of the CREBBP gene, which is involved in regulating cell division and growth.

Multivariate analysis

The application of a statistical method for the simultaneous analysis of more than two variables.

Primary azurophilic granules

Lysosomes found in the cytoplasm of granulocytes that store enzymes, essential for catalysing the 'respiratory burst' of neutrophils that is directed against pathogens or infected cells. The lysosomes are known as 'azurophilic' granules as they are readily stained with azure dyes.

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Melo, J., Barnes, D. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 7, 441–453 (2007). https://doi.org/10.1038/nrc2147

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