Prevention of Chronic Lymphocytic Leukemia (CLL)

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DESCRIPTION (provided by applicant): B-cell chronic lymphocytic leukemia (CLL) is one of the most common forms of leukemia in North America and Europe, accounting for approximately 30% of all cases. Monoclonal B cell lymphocytosis (MBL) has recently been recognized as a potential precursor to CLL and shares phenotypic characteristics with CLL. MBL is present in 3.5% of adults with normal blood counts and 40% of these subjects will have progressive increases in lymphocyte counts. Otherwise healthy subjects in families with 2 or more cases of CLL (familial CLL) have a 7-fold risk of MBL. This supports the hypothesis that there are common factors predisposing to CLL and MBL development and that MBL may be a precursor for CLL. Therefore, it is our hypothesis that identification of factors associated with the transition of MBL to CLL and aggressive early therapy to eradicate MBL in subjects at high risk of developing aggressive CLL with a poor prognosis may prevent death or disability. We believe that development of CLL prevention strategies that center on MBL as a precursor to CLL can be accomplished in three steps. The current application represents the first step in this three-step process. In the first step, phenotypic characteristics that may serve as surrogates for the transition of MBL to CLL will be identified in a pilot study by comparing MBL cells to CLL cells and by longitudinal analysis of MBL cell populations. To date, we have analyzed peripheral blood samples from 45 members of 6 pedigrees with familial CLL. These analyses identified 6 family members with MBL and 2 additional members with previously undiagnosed early CLL. We have developed techniques for analysis of immunoglobulin genes in single MBL cells using flow cytometry, cell sorting and nested PCR. We have also developed techniques for microarray analysis of limited numbers of B cells. We plan to use these and other techniques to perform a pilot study that will determine characteristics of MBL that are associated with transition to CLL by longitudinal analysis of samples from familial MBL subjects.