Mechanisms of transformation by the BCR-ABL oncogene: new perspectives in the post-imatinib era

https://doi.org/10.1016/j.leukres.2003.10.005Get rights and content

Abstract

Since its introduction less than 3 years ago, imatinib mesylate (STI571) has altered the entire approach to the therapy of patients with chronic myeloid leukemia (CML). In addition to its impact on clinical practice, imatinib has also increased the focus of basic and translational CML research on enhancing the cellular effects of imatinib and preventing and overcoming resistance to the drug. Here, I summarize some recent advances in our understanding of the regulatory and signaling mechanisms of Bcr-Abl, with an emphasis on therapeutic implications.

Section snippets

The sensitivity of Abl to imatinib is dictated by the regulatory conformation of the enzyme

To appreciate the dynamics of inhibition of Abl by imatinib it is necessary to understand the regulatory mechanisms governing the catalytic activity of the different forms of the enzyme. It is instructive to consider first the normal c-Abl protein, which has two isoforms (types Ia and Ib) that result from expression of two small alternative first exons. Type Ib c-Abl contains a C14 myristoyl fatty acid moiety covalently linked to the N-terminus and is expressed at higher levels than type Ia,

Mechanism of dysregulation of Abl by fusion of Bcr

While the catalytic activity of c-Abl is tightly controlled within the cell, the Bcr-Abl fusion protein has constitutively high tyrosine kinase activity in vivo and in vitro compared to c-Abl [15]. However, the exact mechanism of dysregulation of Abl kinase activity upon fusion with Bcr has remained unclear despite nearly two decades of intensive research. Relative to c-Abl, the Bcr-Abl fusion protein retains the Abl SH3 domain but lacks Abl first exon sequences and myristoylation and has

The imatinib-sensitive state of Bcr-Abl is monomeric, unphosphorylated, and autoinhibited via the SH3 domain

A recent study has clarified the mechanism of Bcr-Abl regulation by demonstrating that the fusion protein, like c-Abl, is negatively regulated through its SH3 domain [25]. Substitution of alanine for the hydrophobic amino acids at the “a” and “d” positions across the Bcr coiled-coil domain abolishes oligomerization of Bcr-Abl in vivo, and greatly impairs kinase activity in vivo as assessed by phosphotyrosine levels. The low but detectable in vivo tyrosine kinase of monomeric Bcr-Abl may reflect

Bcr-Abl activates many signaling pathways in cell lines, but not all are likely to be relevant to leukemogenesis

Since its discovery over 15 years ago, Bcr-Abl has been intensively studied in cell lines, including human Ph+ cell lines such as K562, and other hematopoietic and non-hematopoietic (e.g. fibroblast) cell lines into which the BCR-ABL gene has been transferred. Because Bcr-Abl is a constitutively active tyrosine kinase, expression of this fusion protein causes activation of a myriad of signaling pathways within the cell, and this has been the subject of several recent and comprehensive reviews

The Grb2–Gab2 connection: an essential signaling pathway downstream of Bcr Tyr177

A good example of the importance of animal models in identifying and validating molecular targets for therapy of CML downstream of Bcr-Abl is the pathway emanating from Tyr177. This residue is highly tyrosine phosphorylated in the active form of Bcr-Abl as a consequence of autophosphorylation and possibly via trans-phosphorylation by Src kinases such as Fps [51]. Phosphorylated Tyr177 forms a high-affinity binding site for the SH2 domain of the adapter protein Grb2 [52], [53]. Mutation of

Summary

The past several years have been marked by extraordinarily rapid progress in the biology and treatment of CML. Imatinib is now the paradigm for molecularly targeted cancer therapy. In reality, imatinib and similar drugs are both therapeutic agents and valuable tools for understanding the molecular pathogenesis of CML. The challenge for the future is to improve upon current clinical results with kinase inhibitor therapy in CML and develop treatment strategies that result in eradication and cure

Acknowledgements

This work was supported by NIH grant CA90576 and a SCOR grant from the Leukemia and Lymphoma Society. The author is a Stohlman Scholar of the Leukemia and Lymphoma Society.

References (63)

  • M Azam et al.

    Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL

    Cell

    (2003)
  • A.M Pendergast

    The Abl family kinases: mechanisms of regulation and signaling

    Adv. Cancer Res.

    (2002)
  • M.W Deininger et al.

    The molecular biology of chronic myeloid leukemia

    Blood

    (2000)
  • T Skorski et al.

    Phosphatidylinositol 3-kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells

    Blood

    (1995)
  • R.L Ilaria et al.

    P210 and P190BCR/ABL induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members

    J. Biol. Chem.

    (1996)
  • C.L Sawyers et al.

    Dominant negative myc blocks transformation by ABL oncogenes

    Cell

    (1992)
  • S Wong et al.

    Cell context-specific effects of the BCR-ABL oncogene monitored in hematopoietic progenitors

    Proc. Natl. Acad. Sci. USA

    (2003)
  • N.P Shah et al.

    Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia

    Cancer Cell

    (2002)
  • R.R Hoover et al.

    Overcoming STI571 resistance with the farnesyltransferase inhibitor SCH66336

    Blood

    (2002)
  • A.M Pendergast et al.

    BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein

    Cell

    (1993)
  • A Goga et al.

    Alternative signals to RAS for hematopoietic transformation by the BCR-ABL oncogene

    Cell

    (1995)
  • Y He et al.

    The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl

    Blood

    (2002)
  • C Kardinal et al.

    Chronic myelogenous leukemia blast cell proliferation is inhibited by peptides that disrupt Grb2-Sos complexes

    Blood

    (2001)
  • M Sattler et al.

    Essential role for Gab2 in transformation by BCR/ABL

    Cancer Cell

    (2002)
  • V Sexl et al.

    Stat5a/b contribute to interleukin 7-induced B-cell precursor expansion, but abl- and bcr/abl-induced transformation are independent of STAT5

    Blood

    (2000)
  • J Schwaller et al.

    et al. STAT5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2

    Mol. Cell

    (2000)
  • R.A Van Etten et al.

    Introduction of a loss-of-function point mutation from the SH3 region of the Caenorhabditis elegans sem-5 gene activates the transforming ability of c-abl in vivo and abolishes binding of proline-rich ligands in vitro

    Oncogene

    (1995)
  • D Barila et al.

    An intramolecular SH3-domain interaction regulates c-Abl activity

    Nat. Genet.

    (1998)
  • B.B Brasher et al.

    Mutational analysis of the regulatory function of the c-Abl Src homology 3 domain

    Oncogene

    (2001)
  • R Plattner et al.

    c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF

    Genes Dev.

    (1999)
  • T Schindler et al.

    Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase

    Science

    (2000)
  • Cited by (0)

    View full text