B-type chronic lymphocytic leukemia (B-CLL) is the most prevalent leukemia in the Western world, occurring most often above the age of 50. DNA sequence analyses indicate that B-CLL cells from unrelated patients share Ig V gene characteristics. Thus, the antigen-receptors of the leukemic cells may be involved in the evolution to malignant clones. However, it is unclear whether these receptor biases are CLL-specific or are phsyiologic , representing a selection for antigens encountered during the normal aging process in the pre-leukemic phase of the cell s development. In support of this latter possibility are data indicating that the B cell repertoire of normal aging controls exhibits Ig VH gene restriction and oligoclonal B cell expansions. This proposal is based on two hypotheses: [1]. that during the normal aging process certain antigens stimulate the expansion of B cell clones expressing receptors similar to those of B-CLL cells and [2]. that it is from this biased pool of clonal expansions that B-CLL cells develop. If true, then these B-CLL- related V genes should be over-utilized in aged individuals and expressed in their clonally-expanded B cells. In addition, these expanded clones should display some of the phenotypic, molecular, and functional properties of B-CLL cells. To test these assumptions, we will: [1]. determine the frequency and diversity of expression of the B-CLL-related V genes in the B cells of normal individuals from birth through advanced age. Special attention will be paid to the genes expressed by the clonal expansions of the elderly; [2]. compare the phenotypic, molecular, and functional characteristics of the clonally- expanded aging B cells with those of B-CLL cells. We will focus on various B-CLL-related characteristics such as surface membrane phenotypes indicative of stages of activation and maturation, V gene mutation status, cell triggering and apoptosis potential, telomere length, and karyotype; and [3]. determine the antigenic reactivities of selected B-CLL cells and of those B cell clones derived from elderly individuals that share V gene structure using a panel of autoantigens, viral proteins, and random peptides generated in phage display libraries. We anticipate that these studies will support a clonal evolution model proceeding from antigenically overexpanded normal aging B cells to a leukemic CCL clone.
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