The Growth Supporting Role of <scp>ZDHHC11</scp> Is Linked to the <scp>MEF2B</scp> – <scp>BCL6</scp> Regulatory Circuit in Burkitt Lymphoma

We previously showed that ZDHHC11 promotes cell growth in Burkitt lymphoma (BL). To explore the underlying mechanism, we performed a genome-wide gene expression analysis upon ZDHHC11 knockdown. We identified MEF2B, a transcription factor critical for germinal center formation, as a downstream target and validated repression of MEF2B at the RNA and protein level upon ZDHHC11 knockdown in BL cell lines. The relevance of MEF2B was shown upon its knockdown, which strongly inhibited growth of BL cells. Since MEF2B is a known regulator of BCL6 in normal GC B-cells, diffuse large B-cell lymphoma, and follicular lymphoma, we subsequently focused on the effect of MEF2B knockdown on BCL6. We observed a strong decrease in BCL6 at the RNA and protein level in BL and showed a strong correlation between MEF2B and BCL6 transcript levels in a panel of B-cell lymphoma cell lines, primary BL samples, and normal B-cell subsets. Knockdown of BCL6 also strongly inhibited growth of BL cell lines, whereas BCL6 overexpression partially rescued the growth-inhibitory effect of MEF2B knockdown. Together, our data indicate that ZDHHC11 promotes BL cell growth at least in part by stimulating expression of MEF2B, which promoted BL cell survival through both BCL6-dependent and independent pathways. Our work highlighted the importance of the MEF2B-BCL6 axis, which strongly supports BL growth and identified ZDHHC11 as a novel regulator of this axis.