Biological Definition of FCRL Molecules in Malignancy

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DESCRIPTION (provided by applicant): B cell chronic lymphocytic leukemia (B-CLL), the most prevalent leukemia in Western countries, is characterized by two subtypes that differ in the mutation status of their immunoglobulin heavy-chain variable region (IgVH) gene. While patients with mutated IgVH genes (MT-CLL) typically have an indolent disease course of greater than 25 years with minimal therapeutic intervention, individuals harboring unmutated IgVH genes (UM-CLL) experience a more aggressive process with a median survival of 8 years even after intensive treatment. Despite these differences, B-CLL cells transcriptionally and phenotypically resemble memory B lineage cells. As genotyping of IgVH regions is costly and technically challenging for most clinical laboratories, surrogate markers for mutation status are being investigated. Expression of the ZAP-70 Syk family tyrosine kinase was found to best correlate with UM-CLL, enabling the stratification of patients into indolent or more aggressive cohorts; however, analysis of this cytoplasmic marker by flow cytometry has created technical challenges resulting in diagnostic variability. The identification of a family of Fc receptor-like molecules (FCRL1-5) with distinct B cell expression and tyrosine-based signaling function opens a new field of study. The long term goal of our studies is to determine the biological role of FCRL molecules in normal immunity and investigate how their functions may be subverted in malignancy. Our preliminary data indicate preferential overexpression of four of five FCRL proteins on MT-CLL. Notably, flow cytometric analysis of the surface expression of FCRL2 on >100 UM-CLL and MT-CLL cell samples indicated strong concordance with MT-CLL and an ability to predict early time to therapy. We hypothesize that FCRL2 can be used as a surrogate prognostic marker in B-CLL and that flow cytometric analysis of cell surface expression of FCRL2 will not only provide a robust assay suitable for clinical laboratories, but will also extend the capabilities of B-CLL diagnosis. This will be tested in two Specific Aims: 1) Optimization of FCRL2 detection on B-CLL cells by flow cytometry and standardization of the assay; and 2) Internal and external validation of the prognostic importance of FCRL2 expression for predicting IgVH mutation status and disease progression in B-CLL. Significance: The assessment of FCRL2 surface expression using routine clinical flow cytometry assays could greatly facilitate prognosis in B-CLL and, thus, significantly improve the overall care of patients with this leukemia. In addition, we anticipate that these studies will extend the capabilities of B-CLL prognosis by providing new insights concerning the aggressive subtype, which ultimately could assist in determination of the optimal timing of therapeutic intervention. PUBLIC HEALTH RELEVANCE: This proposal will investigate the expression of a recently described family of Fc receptor-like molecules (FCRL) in the most prevalent leukemia in Western countries, B cell chronic lymphocytic leukemia (B-CLL). FCRL proteins appear to be preferentially overexpressed in the indolent form of the disease. This work will investigate whether some of these molecules may serve as novel prognostic markers in B-CLL and replace or supplement current indicators of disease aggressiveness.