Dissecting oncogenic signaling by Bcr /Abl and Notch

In leukemia, chromosomal translocations result in oncogene activation. Two outcomes of chromosomal translocation are formation of fusion proteins and inappropriate expression of oncogenes. Here, we study the roles of two chromosomal translocation derived oncoproteins, Bcr/Abl and truncated Notch1, in hematopoietic transformation and development. Bcr/Abl, the product of the t(9; 22) translocation, encodes a fusion oncoprotein with constitutive tyrosine kinase activity. Bcr/Abl is associated with chronic myelogenous leukemia (CML) and is composed of Bcr sequences at the amino-terminus and c-Abl sequences at the carboxyl-terminus. Utilizing a murine CML model to study the role of Bcr in CML pathogenesis, we identified two domains that are required for CML induction: (1) an amino-terminal oligomerization domain and (2) a tyrosine at position 177. These studies provide the basis for investigating the mechanism by which Bcr contributes to CML. Notch1 is a transmembrane protein that functions in cell fate specification. Upon chromosomal translocation, much of the sequences encoding the extracellular domain of Notch1 are removed and the truncated transcript is placed under the transcriptional control of the TCRβ locus. This results in the inappropriately expressed and activated Notch1, which is a transcriptional activator and is associated with T cell lymphocytic leukemia (TALL). Constitutively active Notch signaling promotes ectopic T cell development at the expense of B cell development, and also causes T-ALL in mice. Here, the function of Notch signaling in B cells was assessed. We found that activated Notch1 is a potent inducer of murine B cell death and both cell lines and primary cells were susceptible to Notch killing. The cell death induction was accompanied by upregulation of Hes1 transcript. Overexpression of Hes1 also induced B cell death, suggesting that the activity of Notch in B cells is mediated, at least partially, by Hes1. Additionally, Hes1 overexpression in vivo mimics the activity of Notch in B cells, but fails to induce ectopic T cell development. Thus, signals downstream from Notch have specialized roles in mediating Notch phenotypes. Furthermore, these studies illustrate that the outcome of Notch signaling is cell context dependent