Elsevier

Leukemia Research

Volume 26, Issue 8, August 2002, Pages 713-720
Leukemia Research

Millennium Review
Bcr–Abl variants: biological and clinical aspects

https://doi.org/10.1016/S0145-2126(01)00197-7Get rights and content

Abstract

Bcr–Abl is an oncogene that arises from fusion of the Bcr gene with the c-Abl proto-oncogene. Three different Bcr–Abl variants can be formed, depending on the amount of Bcr gene included: p185, p210, and p230. The three variants are associated with distinct types of human leukemias. Examination of the signaling pathways differentially regulated by the Bcr–Abl proteins will help us gain better insight into Bcr–Abl mediated leukemogenesis.

Introduction

The Philadelphia chromosome (Ph) involves fusion of the breakpoint cluster region (Bcr) gene on chromosome 22 at band q11 with the Abl proto-oncogene on chromosome 9 at band q34 [1]. Three different forms of the Bcr–Abl oncogene exist, p185, p210, and p230, that are associated with distinct types of leukemia. P185 is associated with 20–30% of acute lymphocytic leukemia (ALL), p210 with 90% of chronic myelogenous leukemia (CML), and p230 with a subset of patients with chronic neutrophilic leukemia (CNL) [2]. This review will discuss the biological and clinical aspects of the Bcr–Abl variants.

Section snippets

Clinical correlates

CML typically has a biphasic course that is characterized by chronic and blastic phases [3], [4], [5], [6]. The chronic phase is characterized by an expansion of myeloid cells in the peripheral blood, bone marrow, and spleen. The molecular basis for the myeloid expansion is puzzling as Bcr–Abl transforms the hematopoietic stem cell and is present in all hematopoietic elements [3], [4], [5], [6]. Approximately 50% of patients in the chronic phase have no symptoms and are diagnosed by routine

An overview: Bcr–Abl structure and signaling

The Bcr–Abl fusion protein acts as an onco-protein by activating several signaling paths that lead to transformation. Among these are Myc, Ras, c-Raf, MAPK/ERK, SAPK/JNK, Stat, NFKB, PI-3 kinase, and c-Jun [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61]. Inhibition of Ras [62], Raf [63], PI3K [64], Akt [65], Jun [66], [67], and Myc [68], [69] impairs Bcr–Abl mediated transformation. The oncogenic ability of Bcr–Abl requires deregulated tyrosine kinase activity which leads to

Bcr–Abl variants: molecular structure

Bcr–Abl oncogenes differ in the amount of Bcr included in the fusion protein, and are formed by joining of various amounts of the Bcr gene to the same Abl sequences. This difference in structure influences the biological and clinical phenotypes associated with the Bcr–Abl variants [2]. Splicing at the m, M, or μ breakpoints in Bcr produces three distinct protein products, namely, p185 (e1a2 junction), p210 (b2a2 or b3a2 junction), and p230 (e19a2 junction) (Fig. 1) [2], [97]. P185 encodes the

Bcr–Abl proteins: biological/laboratory correlates

Although the three Bcr–Abl kinases (p185, p210, and p230) are similar in structure, they exhibit distinct properties. When primary mouse bone marrow cells are infected with the different Bcr–Abl variants, and cultured in the presence of cytokines and stroma, p185 cultures differentiate into a lymphoid lineage, whereas p210 and p230 become myeloid [100]. In vitro, p185 has increased ability to stimulate expansion of lymphoid cells, compared to p210 [101]. P230 Bcr–Abl cultures require cytokines

Molecular changes: blastic phase of CML

CML eventually progresses to a blastic phase, reminiscent of acute leukemia that is much more treatment resistant [13], [113]. The molecular changes that accompany this event have been of interest, but are not consistent. Progression to blast crisis has been shown to correlate with the addition of cytogenetic abnormalities such as 22q−, loss of the Y chromosome, isochromosome 17, trisomies-8, -9, -19, an additional Ph chromosome, translocation t(3;21), or inversion of chromosome 16 [13], [114],

Current treatment implications

Traditionally, CML in the chronic phase has been treated with a combination of hydroxyurea and interferon, with a 73% hematologic response rate and 58% rate of cytogenetic remissions [13], [131], [132]. This has been slightly improved with the addition of cytarabine [13]. Despite this, the 5 year survival rates are 57% [131], [132], so allogeneic bone marrow transplant (BMT) has been the treatment of choice for younger patients with an HLA matched identical sibling, showing a 70% cure rate [13]

Acknowledgements

A.S. Advani is supported by National Institutes of Health Training Grant 2-T32-HC07057-26. A.M. Pendergast is supported by National Institutes of Health grants CA61033 and CA70940.

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