BCL11A_XL Protein: Its Distribution in Normal and Malignant Tissues and Use as a Marker for Plasmacytoid Dendritic Cells.

The B-cell lymphoma/leukaemia 11A (BCL11A) gene was first identified in the rare t(2;14)(p16;q32.3) translocation involving the IGH locus in aggressive B-cell chronic lymphocytic leukaemia (CLL) and, together with REL, is a candidate for the 2p16 chromosomal amplifications in B-cell malignancies. BCL11A encodes a Kruppel zinc finger transcription factor essential for pre-B-cell development and thymocyte maturation. Alternative RNA splicing generates at least three BCL11A transcripts encoding proteins that share a common N-terminus with the BCL11A_XL transcript being the most abundant BCL11A transcript in normal tissues. We have produced a murine monoclonal antibody (BCL11A/123, isotype IgG1) specific for the BCL11A_XL protein and, using this reagent, provide the first description of BCL11A_XL protein distribution in normal and malignant human tissues. Initial studies using another antibody to the common N-terminus indicated the BCL11A_XL protein to be the dominant isoform. In lymph node, tonsil and spleen, BCL11A_XL expression was detected in B-cell nuclei in the mantle zone, germinal centers, interfollicular areas, splenic marginal zones and in tonsillar epithelium, but not in plasma cells or T cells. The differential expression of BCL11A_XL in B-cell populations suggests its downregulation might be a requirement for plasma cell differentiation and is consistent with reports that BCL11A is transcriptionally repressed by Blimp-1. A subpopulation of cells, mostly B-cells, in the thymic medulla and scattered cells in the cortex were BCL11A_XL+. Labeling of a very small number of CD3+ T-cells in the cortex and epithelial cells around the cortical periphery was also observed. Labeling of B-cell follicles in rat spleen demonstrated the BCL11A/123 epitope to be conserved across species. Another important finding was the high level expression of BCL11A_XL in CD74+CD68+CD123+ plasmacytoid dendritic cells (pDCs). Publicly available microarray expression data are consistent with these findings, showing BCL11A transcripts to be present at high levels in peripheral blood B cells, in tonsil, lymph node and fetal brain with the highest expression in pDCs. BCL11A_XL therefore represents an additional marker for the identification of pDCs and may be important in the differentiation and/or functional activity of this cell type. BCL11A_XL was commonly detected in B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia and a subgroup of Hodgkin’s lymphomas, with the exception of multiple myeloma. Tumor cells in a small number of T-cell lymphomas (3/29) also expressed BCL11A_XL. In a tissue microarray, comprising 107 cases of de novo DLBCL at diagnosis, BCL11A_XL expression correlated with that of its interaction partner BCL6 and showed a trend towards increased overall survival. The study of this molecule should provide additional invaluable information concerning the possible role of BCL11A in lymphomagenesis.