Chronic myelogeneous leukemia (CML) is a two-stage disease associated with expression of the BCR/ABL tyrosine kinase protein. However, whether BCR/ABL expression directly causes blast crisis, and if so by what mechanism, is unknown. We have found that BCR/ABL translocates from the cytoplasm to the nucleus after genotoxic stress. Furthermore, BCR/ABL increases DNA double-strand damage after etoposide treatment and leads to a defect in an intra-S phase checkpoint, causing a radioresistant DNA synthesis (RDS) phenotype. In the nucleus, BCR/ABL associates with the ataxia-telangiectasia and rad 3-related protein (ATR) and disrupts ATR-dependent signal transduction. Overexpression of ATR in a BCR/ABL-expressing cell line corrects the DNA damage phenotype. These results demonstrate a nuclear role for BCR/ABL in altering the cellular response to DNA damage.
IntroductionTyrosine kinase fusion proteins are the products of a growing family of oncogenes associated with both solid tumors and hematologic malignancies. 1 The best known tyrosine kinase fusion protein is the BCR/ABL tyrosine kinase that results from a t(9;22) translocation in patients with chronic myeloid leukemia. 2 Previous work has demonstrated that BCR/ABL activates multiple signal transduction pathways, including the phosphatidylinositol-3 (PI3) kinase pathway and that transformation by BCR/ABL requires activation of PI3 kinase. [3][4][5][6] To determine if tyrosine kinase fusion proteins share common mechanisms of transformation or if each functions in unique ways, we have chosen to study the TEL/plateletderived growth factor receptor  (PDGFR) fusion protein that results from the t(5;12) translocation in patients with chronic myelomonocytic leukemia. 7 TEL/PDGFR contains the amino-terminal 154 amino acids of TEL fused to the transmembrane and cytoplasmic domains of the PDGFR. TEL is a member of the ETS family of transcription factors and has been described as a common site of rearrangement in multiple forms of leukemia. [8][9][10] Structurally, wild-type TEL contains a 5Ј oligomerization domain, designated the PNT domain; this domain is retained in the fusion protein and is essential for the transforming activity of TEL/PDGFR as demonstrated by us and others. 11,12 Evidence suggests that the PNT domain may cause multimerization of the fusion protein, not simple dimerization. 13 TEL has been reported to induce G1 arrest in vitro 14 and to be required for yolk sac angiogenesis according to murine knockout experiments. 15 PDGFR is a well-characterized plasma membrane receptor with endogenous tyrosine kinase activity that is autophosphorylated in response to binding of dimeric PDGF ligand. 16 In the fusion protein there is retention of the transmembrane domain and the complete tyrosine kinase domain of PDGFR. An intact kinase activity is necessary for transforming activity. 17 The protein retains multiple tyrosine sites that act as binding sites for SH2-containing signaling molecules in the wild type PDGFR. Furthermore, immunolocalization of TEL/PDGFR has demonstrated that the protein is located primarily in the cytosol, retaining neither the nuclear localization of TEL or the plasma membrane localization of PDGFR. 12 Thus, initial models of transformation by TEL/ PDGFR have suggested that the protein is constitutively oligomerized through the TEL PNT domain, leading to constitutive activation of the kinase activity of the 3Ј PDGFR kinase domain and activation of critical signaling pathways. However, the signaling pathways that are necessary for transformation remain undefined.Several signaling pathways have been identified as being activated by TEL/PDGFR. In transformed cell lines, TEL/ PDGFR is known to associate with or cause phosphorylation of phospholipase C (PLC␥1), SHP2, and JNK. 11,18,19 In addition, we have recently shown that TEL/PDGFR activates STAT1 and STAT5 but have been unabl...
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