Prognostic Usage of VH Gene Mutation Status and Its Surrogate Markers and the Role of Antigen Selection in Chronic Lymphocytic Leukemia

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Abstract
B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with many patients surviving for decades with minimal or no treatment, whereas others succumb rapidly to their disease despite therapy. In recent years, new molecular prognostic factors have emerged in CLL that have significantly improved the subgrouping of the disease. One of the most important molecular predictors, the immunoglobulin VH gene mutation status, divides CLL into two prognostic groups, depending on the presence or absence of somatic hypermutation, where unmutated VH genes are associated with considerably worse prognosis than mutated VH genes. An exception to this appears to be CLL patients utilizing the VH3-21 gene as they have poor outcome irrespective of mutation status. Surrogate markers for the VH gene mutation status have been suggested, such as CD38 and ZAP-70 expression. However, the CD38 level was later shown to display poor correlation to the mutation status, although it may still serve as an independent prognostic factor. More promising is the expression levels of ZAP-70, which appears to be both a strong surrogate marker for VH gene mutation status, although discrepancies have been reported, as well as an independent prognostic marker. Immunoglobulin gene analysis has also indicated the possibility of antigen selection in CLL considering the significant bias in VH gene usage. Intriguingly, the VH3-21+ group and several other CLL subsets using certain VH genes was recently reported to display strikingly restricted immunoglobulin gene features, in both their heavy and light chain gene rearrangements, thus further high-lighting the possible role of antigen involvement in CLL development.