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Abstract
Grant Number: 2R37CA049870-17 Project Title: Antibody V Gene Expression B Cell Lymphocytic Leukemia
PI Information: Name Title KIPPS, THOMAS J. tkipps@ucsd.edu POFESSOR/HEAD, DIVISION OF HEMATOLOGY ON Abstract: We have made significant progress in defining the use of immunoglobulin (Ig) variable region genes (V genes) in chronic lymphocytic leukemia (CLL). Prior studies suggesting restriction in the Ig V gene repertoire have been extended, revealing that the Ig expressed in CLL possibly are selected for their ability to bind multiple self-antigens with low affinity. We generated transgenic mice with B cells that express such polyreactive human IgM and found that these cells can differentiate into marginal zone (MZ), memory-type B cells. Such MZ B cells share gene expression profiles with that of CLL cells. These and other newly developed transgenic mouse models of CLL will allow us to evaluate whether Ig receptor signaling plays a role in leukemogenesis and/or disease progression. Recent studies have revealed that patients with CLL cells expressing mutated Ig have a more indolent clinical course that those with CLL cells that express unmutated Ig genes. Gene expression studies revealed that CLL cells expressing unmutated Ig could be distinguished from the more indolent type through the differential expression of a relatively small subset of genes, one of which encodes ZAP-70. We found that CLL cells that express this protein tyrosine kinase have more proficient signaling via the B cell receptor (BCR) complex than CLL cells that do not express ZAP-70. Transfection studies using adenovirus vectors encoding wild type or mutant forms of ZAP-70 are helping to resolve whether ZAP-70 plays a functional role in BCR signaling that can serve as a therapeutic target in this disease. Finally, work on this project has led to development of strategies for inducing anti-leukemia immune responses via the use of CLL cells that are activated via CD40-ligation. Phase I and early phase II clinical trials using recombinant adenovirus vectors encoding a recombinant CD40-ligand (Ad-CD154) are direct manifestations of work performed on this proposal. Further studies could enable us to refine this approach toward development of truly effective immune therapy for patients with this disease.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
B lymphocyte, cellular oncology, chronic lymphocytic leukemia, gene expression, immunoglobulin gene
CD40 molecule, antigen presenting cell, antitumor antibody, autoantibody, disease /disorder model, gene frequency, human population genetics, immunoglobulin structure, molecular oncology, neoplasm /cancer genetics, neoplasm /cancer immunotherapy, neoplastic cell, protein structure function, therapy design /development
clinical research, genetically modified animal, human subject, laboratory mouse, patient oriented research, tissue /cell culture
Institution: UNIVERSITY OF CALIFORNIA SAN DIEGO 9500 GILMAN DR, DEPT 0934 LA JOLLA, CA 920930934 Fiscal Year: 2004 Department: MEDICINE Project Start: 21-SEP-2004 Project End: 31-JUL-2009 ICD: NATIONAL CANCER INSTITUTE IRG: CII