Functional studies of BCL11A: a transcriptional repressor implicated in chromosome 2p13-disrupted malignancy

Access full-text files




Liu, Hui

Journal Title

Journal ISSN

Volume Title



Many malignancies of mature B lymphocytes are characterized by chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus on chromosome 14q32.2, resulting in the deregulation of the translocated proto-oncogene. Although t(2;14)(p13;q32.3) is a rare event in B cell malignancies, gains and amplifications of chromosome 2p13 have been reported in 20% of extranodal B cell non-Hodgkin’s lymphoma (B-NHL) and in Hodgkin’s disease (HD). In previous studies, we have identified a novel Krüppel zinc finger gene BCL11A and showed it to be disrupted and deregulated in four cases of B cell malignancies with t(2;14)(p13;q32.3). Three major alternatively spliced isoforms of BCL11A have been detected: BCL11Axl (~120 kD), BCL11Al (~100 kD) and BCL11As (~30 kD). All three mRNAs were upregulated as a consequence of the t(2;14)(p13;q32). Here we confirm that at the protein level, BCL11A isoforms are overexpressed in malignant cells in which the 2p13 locus is genetically disrupted. We also demonstrate that within normal immune tissues, BCL11A accumulates preferentially in germinal centers. In addition, all three isoforms can physically interact with each other. Both BCL11Axl and BCL11Al can colocalize and physically interact with another human B cell proto-oncogene BCL6. BCL11A isoforms potentiate transcriptional repression activity, which is trichostatin A and BCL6 independent. BCL11Axl and BCL11Al but not BCL11As can induce apoptosis in both lymphoid and nonlymphoid cell lines. The apoptotic effect is independent of BCL6, but can be moderately enhanced by p53, and completely blocked by the overexpression of Bcl-2 or a caspase-9 inhibitor. Potential target genes for BCL11Axl were identified by screening Lymphochip microarrays. 28 out of 39 target genes were down-regulated by BCL11Axl. A number of genes functioning in signal transduction, cell cycle control and apoptosis were identified, including Akt2, ATR, Trio, NFκB, and MDM2. Based on the data cited above, we propose that BCL11A induces apoptosis through blockage of the PI3K-Akt cell survival pathway. Although the mechanism by which deregulated BCL11A causes B cell malignancies remains elusive, we suggest that the inhibition of cell cycle checkpoint pathways and Rac-Rho signaling pathways via down regulation of ATR and Trio might play critical roles in BCL11A tumorigenesis.





LCSH Subject Headings