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
journal contributionposted on 24.10.2012, 09:14 by H. Liu, G. C. Ippolito, J. K. Wall, T. Niu, L. Probst, B.-S. Lee, K. Pulford, A. H. Banham, Luke Stockwin, A. L. Shaffer, L. M. Staudt, C. Das, Martin J. S. Dyer, P. W. Tucker
Background: Chromosomal aberrations of BCL11A 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 BCL11A produces multiple isoforms sharing a common N-terminus. The most abundant isoform we have identified in human lymphoid samples is BCL11A-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 BCL11A-XL is a DNA-sequence-specific transcriptional repressor that associates with itself and with other BCL11A isoforms, as well as with the BCL6 proto-oncogene. Western blot data for BCL11A-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 BCL11A-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. BCL11A-XL partitions into the nuclear matrix and colocalizes with BCL6 in nuclear paraspeckles. Conclusion: We propose that the conserved N-terminus of BCL11A defines a superfamily of C2HC zinc-finger transcription factors involved in hematopoietic malignancies.