Epigenetic Mechanisms of Therapy Resistance in Diffuse Large B Cell Lymphoma (DLBCL)

Diffuse large B cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin B cell lymphoma (NHL), and manifests highly heterogeneous genetic/phenotypic characteristics as well as variable responses to conventional immunochemotherapy. Genetic profiling of DLBCL patients has revealed highly recurrent mutations of epigenetic regulator genes such as CREBBP, KMT2D, EZH2 and TET2. These mutations drive malignant transformation through aberrant epigenetic programming of B-cells and may influence clinical outcomes. These and other chromatin modifier genes also play critical roles in normal B-cells, as they undergo the various phenotypic transitions characteristic of the humoral immune response. Many of these functions have to do with impairing immune surveillance and may critically mediate resistance to immunotherapies. In this review, we describe how epigenetic dysfunction induces lymphomagenesis and discuss ways of implementing precision epigenetic therapies to reverse these immune resistant phenotypes.