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Despite a large effort, there is no realistic transgenic model of BCR– ABL-induced CML ( van Etten, 2001). In order to express BCR– ABL directly in the hematopoietic system of mice, both transgenic and retroviral transduction approaches have been employed.
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Expression of BCR– ABL in ES cells alters the balance of in vitro erythroid differentiation towards myeloid and multipotential progenitors ( Era and Witte, 2000) and permits multilineage engraftment of irradiated recipient mice by differentiated ES cells ( Perlingeiro et al., 2001), but the hematologic disease that develops in recipients is not an accurate representation of human CML ( Peters et al., 2001). Furthermore, while murine embryonic stem (ES) cells can undergo differentiation in vitro to all myeloid lineages, studies of BCR– ABL activity in ES cells have not provided major insights into leukemogenesis. For example, although the hallmark of human chronic myeloid leukemia (CML) is an overproduction of myeloid cells with preservation of myeloid differentiation, expression of BCR– ABL in 32D cells, which can undergo terminal granulocytic differentiation in response to G-CSF, blocks the ability of these cells to differentiate ( Laneuville et al., 1991). Although cell lines do exist that recapitulate some aspects of hematopoietic differentiation in vitro, these may not be appropriate systems for the analysis of BCR– ABL activity. This is because the complex nature of leukemia cannot be adequately modeled in any currently existing cell culture system. Studies with inhibitors and dominant-negative mutants have suggested that several of these pathways contribute to transformation of fibroblasts or hematopoietic cells by Bcr–Abl in vitro ( Dickens et al., 1997 Nieborowska-Skorska et al., 1999 Reuther et al., 1998 Sawyers et al., 1992, 1995 Raitano, 1995 Skorski et al., 1995a, b).Īlthough much has been learned about the biology of BCR– ABL through these studies, a complete understanding of the pathophysiology of BCR– ABL-associated leukemias requires the expression of the oncogene in the hematopoietic system of a living organism. Studies in cultured cells have identified many signal transduction pathways activated by Bcr–Abl, including activation of Ras ( Sawyers et al., 1995), MAPK ( Cortez et al., 1997), JNK/SAPK ( Raitano et al., 1995), phosphatidylinositol-3 kinase ( Skorski et al., 1995a Varticovski et al., 1991), NF-κB ( Reuther et al., 1998), and STAT pathways ( Carlesso et al., 1996 Ilaria and van Etten, 1996 Shuai et al., 1996). The primary structures of the Bcr and Abl polypeptides have been analyzed and dissected in great detail, with the elucidation of an oligomerization domain ( Mcwhirter et al., 1993), Grb2 binding site ( Pendergast et al., 1993b Puil et al., 1994), serine kinase activity ( Maru and Witte, 1991) and regulatory phosphorylation sites ( Liu et al., 1996 Wu et al., 1998), SH2 binding domain ( Pendergast et al., 1991) and Dbl homology in Bcr and description of N-terminal SH3 ( Franz et al., 1989 Jackson and Baltimore, 1989 van Etten et al., 1995), SH2 ( Ilaria and van Etten, 1995 Mayer et al., 1992) and catalytic domains ( Pendergast et al., 1993a) and C-terminal adapter protein binding sites ( Ren et al., 1994), nuclear localization signals ( Wen et al., 1996) and DNA-binding ( Kipreos and Wang, 1992) and actin-binding ( Mcwhirter and Wang, 1993 van Etten et al., 1994) domains in Abl.
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Through these studies, we know that Bcr–Abl has increased tyrosine kinase activity relative to c-Abl ( Ilaria and van Etten, 1995 Lugo et al., 1990) and has gained the ability to transform fibroblasts ( Lugo and Witte, 1989), cytokine-dependent hematopoietic cell lines ( Daley and Baltimore, 1988 Hariharan et al., 1988), and primary bone marrow B-lymphoid cells ( Mclaughlin et al., 1987).
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The molecular biology of BCR– ABL and its protein product, the Bcr–Abl tyrosine kinase, have been intensively analysed in cell culture systems since the discovery of the fusion oncogene nearly 18 years ago.