IL-7, initially described as a B-lineage growth factor, has been demonstrated to stimulate proliferation and induce signal transduction events in both B and T-cell progenitors, myeloid cells, mature T-cells, and a variety of patients leukemia and lymphoma cells. Recent studies have demonstrated that the IL7R complex consists of at least two subunits, one being a p64 protein shared among the IL2R, Il4R and IL7R complexes. Intracellular events associated with IL7R engagement include tyrosine phosphorylation on a number of proteins, stimulation of phosphatidylinositol kinase, and induction of expression of a number of early response genes, including c-myc and c-jun. The recent demonstration of constitutive IL7 secretion and development of IL7R antagonist agents might b of clinical use in the therapy of a variety of hematopoietic neoplasms. To date, different IL7 receptor isoforms have been identified in the context of resting and activated normal T-lymphocytes, but isoform composition and its relationship to receptor affinity aha not been clearly defined in neoplastic lymphocytes.
The aim of this proposal is to further characterize the native IL7R isoforms and biological correlates of ligand- receptor binding on neoplastic lymphocytes from a series of patients with leukemias and lymphomas. In order to better understand properties of the ligand and its receptor important to its biological activity, a number of candidate IL7 mutants will be utilized, to define the receptor-binding and signal transducing domains of the cytokine, and a series of chimeric ligand fusion toxins will be used to define the requirements for ligand-receptor internalization in both normal and neoplastic lymphocytes. This work will be conducted in collaboration with Dr. John Murphy, who will generate the candidate mutants and fusion toxins.
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