Functional studies of BCLIIA: Characterization of the conserved BCLIIA-XL splice variant and its interaction with BCL6 in nuclear paraspeckles of germinal center B cells

Background: Chromosomal aberrations of BCLIIA at 2p16.1 have been reported in a variety of B-cell malignancies and its deficiency in mice leads to a profound block in B-cell development. Results: Alternative pre-mRNA splicing of BCLIIA produces multiple isoforms sharing a common N-terminus. The most abundant isoform we have identified in human lymphoid samples is BCLIIA-XL, the longest transcript produced at this locus, and here we report the conservation of this major isoform and its functional characterization. We show that BCLIIA-XL is a DNA-sequence-specific transcriptional repressor that associates with itself and with other BCLIIA isoforms, as well as with the BCL6 proto-oncogene. Western blot data for BCLIIA-XL expression coupled with data previously published for BCL6 indicates that these genes are expressed abundantly in germinal-center-derived B cells but that expression is extinguished upon terminal differentiation to the plasma cell stage. Although BCLIIA-XL/BCL6 interaction can modulate BCL6 DNA binding in vitro, their heteromeric association does not alter the homomeric transcriptional properties of either on model reporter activity. BCLIIA-XL partitions into the nuclear matrix and colocalizes with BCL6 in nuclear paraspeckles. Conclusion: We propose that the conserved N-terminus of BCLIIA defines a superfamily of C2HC zinc-finger transcription factors involved in hematopoietic malignancies.