Mechanisms of BCR-ABL in the Pathogenesis of Chronic Myelogenous Leukemia

Ruibao Ren

In This Article

Abstract and Introduction

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?

Chronic myelogenous leukaemia (CML) results from the neoplastic transformation of a haematopoietic stem cell (Fig. 1). The hallmark genetic abnormality of CML is a t(9;22)(q34;q11) translocation, which was first discovered as an abnormal, small chromosome, named the 'Philadelphia chromosome'. This translocation generates the BCR - ABL fusion gene (reviewed in Ref. [1]). The initial chronic phase of this biphasic disease is characterized by a massive expansion of the granulocytic cell lineage, even though most, if not all, haematopoietic lineages can be produced from the CML stem cell. The median duration of the chronic phase is 3-4 years. Acquisition of additional genetic and/or epigenetic abnormalities causes the progression of CML from chronic phase to blast phase. This phase is characterized by a block of cell differentiation that results in the presence of 30% or more myeloid or lymphoid blast cells in peripheral blood or bone marrow, or the presence of EXTRAMEDULLARY infiltrates of blast cells.

The development of chronic myelogenous leukaemia.
Chronic myelogenous leukaemia (CML) is a biphasic disease, initiated by expression of the BCR - ABL fusion gene product in self-renewing, haematopoietic stem cells (HSCs). HSCs can differentiate into common myeloid progenitors (CMPs), which then differentiate into granulocyte/macrophage progenitors (GMPs; progenitors of granulocytes (G) and macrophages (M)) and megakaryocyte/erythrocyte progenitors (MEPs; progenitors of red blood cells (RBCs) and megakaryocytes (MEGs), which produce platelets). HSCs can also differentiate into common lymphoid progenitors (CLPs), which are the progenitors of lymphocytes such as T cells and B cells. The initial chronic phase of CML (CML-CP) is characterized by a massive expansion of the granulocytic-cell series. Acquisition of additional genetic mutations beyond expression of BCR-ABL causes the progression of CML from chronic phase to blast phase (CML-BP), characterized by an accumulation of myeloid (in approximately two-thirds of patients) or lymphoid blast cells (in the other one-third of patients). Although the CML stem cell is multipotent, production of B cells from the neoplastic clone occurs only at low levels, and only rare T-cell precursors can be detected. This indicates that lymphopoiesis, particularly the development of T cells, is compromised by BCR-ABL expression.[118]

Allogeneic stem-cell transplantation is the only known curative therapy for CML. However, most patients are not eligible for this therapy, because of advanced age (making them unable to tolerate the serious side effects of the treatment) or lack of a suitable stem-cell donor (reviewed in Ref. [2]). The discovery that BCR-ABL is required for the pathogenesis of CML, and that the tyrosine-kinase activity of ABL is essential for BCR-ABL-mediated transformation, made the ABL kinase an attractive target for therapeutic intervention (reviewed in Ref. [3]). Imatinib mesylate (Glivec, previously known as STI571 and CGP 57148) — a potent inhibitor of the tyrosine kinases ABL, ARG, platelet-derived growth factor receptor and KIT — has been shown to selectively induce apoptosis of BCR-ABL+ cells,[4,5,6,7] and is remarkably successful in treating patients with CML (reviewed in Ref. [8]). In newly diagnosed patients with CML in chronic phase, imatinib induces COMPLETE CYTOGENETIC RESPONSE in more than 80% patients. Patients with more advanced phases of CML also respond to imatinib, but this occurs much less frequently and treatment is less durable.[8]

However, there are two major obstacles to imatinib-based therapies for patients with CML. One is the persistence of BCR - ABL -positive cells — this is known as 'residual disease', and is detected by a sensitive nested reverse-transcriptase PCR assay.[9,10,11] Suppression of the disease therefore relies on continuous imatinib therapy. The other major problem is relapse of the disease due to the emergence of resistance to imatinib (reviewed in Ref. [12]). Several mechanisms of resistance have been described, the most frequent of which are the appearance of point mutations in the BCR - ABL gene that impair the drug binding (comprehensively reviewed elsewhere)[12,13,14].

The fact that the resistance to imatinib is most commonly associated with point mutations in the kinase domain of BCR-ABL further demonstrates the importance of this activity in the pathogenesis of CML. On the other hand, the persistence of BCR - ABL -positive cells in patients on imatinib therapy indicates that inhibition of the ABL kinase activity alone might not be sufficient to eradicate the leukaemia cells. Identification of additional essential components in the pathogenesis of CML remains crucial for developing improved therapies for CML.

Numerous signalling pathways are active in BCR-ABL-expressing cells. Most of these were discovered through analysis of cultured cells. But the development of CML is a complex process that involves not only the signalling pathways mediated by BCR-ABL, but also factors provided by host cells and other components of the in vivo environment. It is therefore important to identify and validate potential therapeutic targets involved in BCR-ABL leukaemogenesis in vivo . What have studies in mouse models taught us about CML pathogenesis, response to therapy and mechanisms of minimal residual disease?


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