Division of labor for oncogene BCL6

In this issue of Blood, Parekh and colleagues provide the first evidence that BCL6 uses different corepressor proteins for different functions. BCL6 requires the Mta3 corepressor to control B-cell differentiation, but not to control cell proliferation and survival. BCL6 is tightly linked to the pathogenesis of diffuse large B-cell lymphoma, and this work has implications for the development of therapies that target BCL6 function.

Chromosomal translocations and point mutations involving the promoter of the BCL6 gene are extremely common in diffuse large B-cell lymphomas. These BCL6 gene translocations and mutations alter normal BCL6 gene transcription by removing or mutating negative regulatory elements. Normally, BCL6 is expressed at high levels in actively proliferating germinal center B cells, and BCL6 transcription is turned off during plasma-cell differentiation. Deregulated BCL6 expression due to translocations and gene mutations is thought to keep B cells in a rapidly proliferating germinal-center–like state and to promote the process of B-cell transformation. In mouse model systems, constitutive expression of BCL6 can immortalize primary B cells and promote the development of lymphomas, proving that BCL6 can act as an oncogene.

A central issue for BCL6 research is determining which target genes repressed by BCL6 are critical for B-cell transformation. A handful of known BCL6 target genes regulate cell growth, survival, and differentiation—all hallmark processes in cellular transformation. One prominent target gene by which BCL6 can regulate B-cell differentiation is PRDM1 (Blimp1), the master regulator of plasma-cell differentiation.¹  Repression of PRDM1 provides a direct link between BCL6 and inhibition of plasma-cell differentiation. Repression of the BCL6 target genes p21^cip1, p27^kip1, and p53 promote cell proliferation and cell survival.^1–3 

The paper by Parekh and colleagues in the current issue follows up on earlier work by Fujita et al,⁴  who showed that the interaction between BCL6 and the Mta3 corepressor protein is critical for inhibition of plasma-cell differentiation by BCL6. Parekh and coworkers show that BCL6 and Mta3 expression levels are tightly linked in human lymphoma, and that Mta3 and BCL6 both bind to a regulatory element in the PRDM1 gene. The surprising result came from siRNA-mediated knockdown experiments of Mta3 in lymphoma cells, where loss of Mta3 expression led to derepression of PRDM1 and differentiation of the cells into plasmacytoma-like cells. However, knockdown of Mta3 did not affect the expression of the BCL6 target gene p53 and did not affect lymphoma-cell survival or proliferation. These results dovetailed with further experiments showing that inhibition of other BCL6 co-repressors besides Mta3 led to a decrease in lymphoma-cell survival and proliferation. Overall, these results indicate a fascinating segregation of repressor function for BCL6, where one set of BCL6 corepressor proteins (Mta3) controls genes involved in B-cell differentiation and another set of BCL6 corepressor proteins (NcoR, BcoR, SMRT) controls genes involved in B-cell proliferation and survival (see figure). While more work is required to confirm and extend these results to other target genes, the results of Parekh and colleagues nonetheless have clear implications for the design of drugs that target BCL6 function in B-cell lymphoma. Accordingly, Parekh and colleagues showed that inhibition of both BCL6 corepressor pathways resulted in a synergistic negative effect on the survival of a B-cell lymphoma line in vitro. Thus, all modes of BCL6 action need to be targeted for effective therapy of BCL6-associated diffuse large B-cell lymphoma.