Growth factor independence and BCR/ABL transformation: promise and pitfalls of murine model systems and assays

Abstract

The expression of the BCR-ABL fusion oncoprotein in primitive hematopoietic cells results in chronic myeloid leukemia. Over the past decade studies of several in vitro and in vivo cell systems revealed multiple signal transduction pathways activated by BCR-ABL. However, the precise function of BCR-ABL in the pathogenesis of CML is still unclear. The goal of this review is to synthesize data on intracellular signaling in the context of the diverse murine assay systems employed. We emphasize the importance of in vivo assays and assays using primary cells in understanding the biology of CML and the molecular mechanisms by which BCR-ABL exerts its effects.

Protein kinase CKIIα interacts with the Bcr moiety of Bcr/Abl and mediates proliferation of Bcr/Abl-expressing cells

“…In contrast, we found that inhibition of Bcr/Abl inhibited CKIIa activity. These disparate results are difficult to compare because very different experimental conditions were used: at least in other systems, outcome of growth factor independence and transformation studies by Bcr/Abl have been shown to be cell-type-and assay-dependent (Ghaffari et al, 1999). Similar to our study, others have also found a transformation-stimulatory cooperation between CKIIa and other oncogenes.…”

A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation

“…This hypothesis remains to be proven, although the existence of a rapamycin-resistant kinase, which contributes to phosphorylation of 4E-BP1, is suggested by the work of others using a dominantnegative form of mTOR (Edinger et al, 2003). Our data also demonstrate that yet another common target of cytokine-and Bcr-Abl-mediated signaling is 4E-BP1 (Figures 1c and 3c), and is in line with the prevailing understanding that Bcr-Abl-containing malignancies 'co-opt' existing cytokine-mediated signaling pathways to gain a proliferative/survival advantage over their normal counterparts (Ghaffari et al, 1999;Deininger et al, 2000). In primary CML cells, we observed that the effect of imatinib on inhibiting 4E-BP1 phosphorylation and induction of eIF4F was less dramatic than in Ba/ F3-Bcr-Abl and K562 cells, although combined inhibition of Bcr-Abl and mTORC1 was still required for maximal inhibition of 4E-BP1 phosphorylation, eIF4F formation and cyclin D3 protein expression (Figures 1d, 4 and 5f).…”

Molecular and cellular bases of chronic myeloid leukemia

“…The existence of unknown genetic abnormalities in established cell lines might also obscure the function of the gene studied. Inconsistent results have been obtained from cell line studies in assessing the role of certain functional domains or motifs, such as the GRB2 SH2-binding site at Y177 of BCR and of the SH2 domain of ABL, in transformation by BCR-ABL (Ghaffari et al, 1999). Deletion of the SH3 domain of ABL results in a mutant form of the protein with increased tyrosine kinase activity, and expression of this truncated protein can transform both fibroblast and haematopoietic cell lines in vitro.…”