A subset of human T-ALLs are associated with a (7;9) chromosomal translocation that juxtaposes the 3' end of the Notch1 gene to the T-cell receptor beta locus. As a result, rumors with the (7;9) overexpress tumor-specific polypeptides comprised of just the intracellular portion of the Notch receptor protein. The normal Notch receptor plays an important role in controlling the differentiation of many kinds of cells, including T cells, by participating in a novel signal transduction pathway triggered by binding of ligand to the extracellular domain of Notch1 that eventuates in the activation of the transcription factor RBP-Jk. Polypeptides resembling the t(7;9)-specific forms of Notch1 have constitutive signaling activity, suggesting that the leukemogenic effect of Notch1 is mediated by an increase in signaling, possibly through RBP-Jk. It is the goal of our labs to understand the mechanism by which Notch1 directs malignant tranformation in hematopoietic cells in vivo. To this end, we have developed a murine model that reliably reproduces the Notch1-induced T-ALL within 6 weeks following transplanation of Notch-1 transduced bone marrow cells. In this proposal, we will utilize this model together with in vitro studies to investigate the pathogenesis of Notch1 T-ALL. The described studies will: I) identify the minimal transforming region of Notch1, ii) identify the signaling pathways involved in Notch1 T-ALL, iii) identify the role of subcellular localization of Notch1 in leukemic induction, and iv) to begin to determine the basis for the T-cell oncotropicity of Notch1. These studies will lead to an improved understanding of how Notch1 causes leukemic transformation, and may identify new therapeutic targets.
Showing the most recent 10 out of 16 publications
