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Epigenetic Basis and Therapy of DLBCL
Some mutations of transcription factors and chromatin modifiers are a genetic hallmark of DLBCLs regardless of subtype. Most DLBCLs arise from B cells transposing the germinal center reaction the humoral immune response. During this process B cells undergo a series of rapid phenotypic changes, induce through the immune synapse they form with specialized follicular helper (THF cells). During their proliferation burst, germinal center B-cells downregulate many immune synapse genes which allows them to undergo somatic hypermutation without
interruption. Somatic mutations that impair expression of subsets of immune synapse genes lead to development of GCB-DLBCLs, whereas mutations that hijack and enhance immune synapse genes lead to ABC-DLBCLs. In GCB-DLBCLs impaired expression of immune synapse genes is often
due to mutations in chromatin modifiers EZH2, CREBBP, KMT2D, ARID1A, etc. Each of these genes have specific and dispositional biochemical functions and caused somewhat different phenotypes that cause immune evasion and shape the lymphoma immune microenvironment in different ways.
Novel selective therapeutic agents now exist to counteract each of these four classes of chromatin modifiers, enable the immune system to re-engage and kill these lymphomas and potently enhance the activity of immunotherapies, which if properly sequenced and dosed may have profound anti-lymphoma activity. Although chromatin modifiers are not often mutated in ABC-
DLBCL, the effect of canonical mutations in signaling genes such as MYD88L256P ultimately mediate
their effects by reprogramming the epigenome of B cells, favoring emergence of aberrant transcriptional programs, such as the TBET autoimmune B cell program. These mechanisms also
provide opportunities for novel epigenetic therapeutic interventions. Here, we will review these concepts with a view towards how lymphomas may be eradicated by re-establishing proper control of immune surveillance genes and other functions.
Speakers
Ari Melnick