This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in the western world, and the incidence of this disease is increasing yearly.1 CLL generally follows an indolent clinical course affecting mainly elderly patients, with a median age at presentation of greater than 65 years. Many such patients will not require therapy. However, the disease is heterogeneous, and some patients have a more aggressive clinical course.2,3 To estimate prognosis in CLL, two major staging systems( Rai and Binet ), mainly based on tumor load, are used.4,5 These systems define distinct prognostic subgroups, but their ability to predict the outcome of individual patients at the time of diagnosis, is limited. Therefore, other factors related to the biology of CLL, such as genetic markers, as well as cellular and molecular features, are currently being evaluated for their prognostic impact. An interesting genetic marker, related to the stage of B-cell differentiation, is provided by the recombination of variable (V), diversity (D), and joining (J) immunoglobulin gene segments and the process of somatic hypermutation, which physiologically occurs in the germinal center.6 Although the B-CLL cells were originally considered to correspond to antigen-inexperienced pregerminal center lymphocytes, recent data indicates that in approximately half of all cases, somatically mutated variable region heavy chain genes (VH) are present.7,8 In pivotal studies correlating the IgVH mutation status with survival probability, the presence of unmutated IgVH predicted for an inferior clinical course in CLL.9,10 In one of these studies, a high CD38 expression level was found to correlate with the presence of unmutated IgVH genes and an unfavorable clinical outcome,10 but the relation of CD38 expression to IgVH mutation status and survival is the subject of controversial discussion.11-13 A new study, using gene expression profiling by microarray analysis in patients with CLL, has shown a strong correlation between unmutated IgVH status and expression of a tyrosine kinase called Zap-70, which can be used to define the presence of unmutated IgVH genes.Objectives:Primary: A prospective study of CLL patients to assess the correlation of immunophenotype including CD38 expression and Zap-70 with change in disease status, defined as change in stage, need for treatment, transformation, or infection.Secondary:1 The prospective impact of CD38 expression and Zap-70 expression on response to treatment.2 The relation of CD38 expression to Zap-70 expression and overall survival.3 To assess the change in gene expression profiling using DNA microarray analysis in CLL patients at the time of disease progression and transformation.
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