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  • Review Article
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Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia

Nature Reviews Cancer volume 5, pages 172–183 (2005)Cite this article

Key Points

  • Chronic myelogenous leukaemia (CML) results from the neoplastic transformation of a haematopoietic stem cell. Clinical and laboratory studies indicate that the fusion protein BCR–ABL is essential for initiation, maintenance and progression of CML, yet the transformation of CML from chronic phase to blast phase requires additional genetic and/or epigenetic abnormalities.

  • Imatinib — an inhibitor of the tyrosine-kinase activity of BCR–ABL — has been successfully used to treat patients with chronic-phase CML, but residual disease persists and drug resistance emerges. It is therefore important to identify other factors involved in the pathogenesis of CML, to design alternative treatment strategies.

  • Transgenic expression of BCR–ABL in mice leads to a myeloproliferative disorder that resembles the chronic phase of CML in patients. The ABL tyrosine-kinase activity is necessary but not sufficient to induce CML-like disease in mice. So, additional activities of BCR–ABL, beyond its kinase activity, are important for leukaemogenesis.

  • BCR–ABL also interacts with oncogenic transcription factors to induce a form of acute myelogenous leukaemia that resembles the blast phase of CML, indicating that disease progression involves cooperation between BCR–ABL and mutations that disrupt haematopoietic gene transcription.

  • CML progenitor cells seem to be refractory to imatinib therapy, indicating that the biology of haematopoietic stem/progenitor cells and tumour microenvironment are likely to contribute to the disease development and maintenance.

Abstract

Imatinib, a potent inhibitor of the oncogenic tyrosine kinase BCR–ABL, has shown remarkable clinical activity in patients with chronic myelogenous leukaemia (CML). However, this drug does not completely eradicate BCR–ABL-expressing cells from the body, and resistance to imatinib emerges. Although BCR–ABL remains an attractive therapeutic target, it is important to identify other components involved in CML pathogenesis to overcome this resistance. What have clinical trials of imatinib and studies using mouse models for BCR–ABL leukaemogenesis taught us about the functions of BCR–ABL beyond its kinase activity, and how these functions contribute to CML pathogenesis?

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Figure 1: The development of chronic myelogenous leukaemia.
Figure 2: The ABL and BCR proteins.
Figure 3: Leukaemogenic signalling of BCR–ABL.

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Acknowledgements

I would like to apologize for not being able to cite all the relevant literature owing to limited space. I would also like to acknowledge grants from the National Cancer Institute and the American Cancer Society.

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Authors and Affiliations

  1. Rosenstiel Basic Medical Sciences Research Center, MS029, Brandeis University, 415 South Street, Waltham, 02454-9110, Massachusetts, USA

    Ruibao Ren

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  1. Ruibao Ren
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DATABASES

Entrez Gene

ABL

AML1

ARG

BCR

BRAF

CBFβ

CDKN2A

EVI1

GAB2

GRB2

HOXA9

ICSBP

JUNB

KRAS

MOZ

MYC

NRAS

NUP98

RB

SHIP

SHP2

SIPA1

SMMHC

SOS

TIF2

TP53

National Cancer Institute

acute myelogenous leukaemia

chronic myelogenous leukaemia

OMIM

Noonan syndrome

FURTHER INFORMATION

Cancer medical terms

Glossary

EXTRAMEDULLARY

Outside the bone marrow, as in the spleen, liver or lymph nodes.

COMPLETE CYTOGENETIC RESPONSE

Mononuclear bone-marrow cells shown to be negative for t(9;22)(q34;q11), as determined by cytogenetic analysis or fluorescence in situ hybridization analysis.

CD34

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

MYELOPROLIFERATIVE DISORDER

Characterized by high peripheral-blood counts with granulocyte predominance, hepatosplenomegaly (enlarged liver and spleen) and pulmonary haemorrhages, owing to extensive granulocyte infiltration.

B-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA

Characterized by high peripheral-blood cell counts, bloody pleural effusion (chest-cavity fluid) that contains B-lymphoblastic cells, and an enlarged lymph node.

T-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA

Characterized by high peripheral-blood cell counts, bloody pleural effusion that contains T-lymphoblastic cells and enlarged thymus.

THROMBOCYTOSIS

Increased numbers of platelets in the peripheral blood.

INTERLEUKIN-3

A haematopoietic growth factor that promotes survival and activation of many lineages of cells in the haematopoietic system — particularly in mast and basophil development and immunity in cases of parasitic infection.

GRANULOCYTE COLONY-STIMULATING FACTOR

Also known as granulocyte growth factor, it is important for the development of neutrophils and haematopoietic progenitors.

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Ren, R. Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5, 172–183 (2005). https://doi.org/10.1038/nrc1567

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