Recent evidences revealing that germinal center B-cells (GCB cells) are the cellular origin of HRS cells [294], and the facts that PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in both activated B cell-like (ABC) and GCB cells of diffuse large B cell lymphoma (DLBCL) [297] suggest that PI3K/AKT may promote lymphomagenesis of GCB cells in HL, which is a remarkable coincidence with the other evidences that the PI3K/AKT pathway plays a pathogenetic role in HL [298, 299]. This evidence concerns the gene PRMT5 and diffuse large B-cell lymphoma.