Mechanisms associated with noninflamed lymphoma environments. (A) Double-hit lymphomas or those expressing a so-called double-hit gene signature exhibit strong cell autonomous growth and survival programs and are often characterized by an intrinsically high proliferation rate, which may function to exclude immune cells from entering the lymphoma environment, thereby preventing the generation of a host antilymphoma immune response. (B) Activating EZH2 mutations lead to increased deposition of repressive histone marks (H3K27me3) on genes involved in B-cell differentiation, expression of HLA class I and class II molecules, and expression of chemokines required to recruit activated T cells to the lymphoma environment, rendering the host immune system ignorant to the presence of these tumors.