Figure 4.

Disrupted signaling pathways in GCB-DLBCL. Genetic lesions preferentially associated with GCB-DLBCL include (i) chromosomal translocations of BCL2 (up to 35% of cases) and/or MYC (∼10% of cases), which lead to their ectopic expression in part by allowing them to bypass BCL6-mediated transcriptional repression; (ii) truncating mutations of the TNFRSF14 receptor, leading to weakened T-cell responses; (iii) gain-of-function mutations of EZH2 (∼20% of cases), which induce transcriptional silencing of various antiproliferative and tumor suppressor genes, including targets common to BCL6 (eg, CDKN1A and BLIMP1); (iv) point mutations in the BCL6 autoregulatory sequences (10% of cases). In addition, loss of PTEN expression is observed in as many as 55% of cases, as a consequence of genetic deletions (15%) and amplifications of miR17-92 (29%), resulting in activation of the PI3K/Akt/mTOR signaling pathway. Targeted agents currently in clinical trial (or, for BCL6, demonstrating activity in preclinical settings) are shown in red.