Year: 2023
Type: article
Abstract: Somatic mutations of transcription factors and chromatin modifiers are a genetic hallmark of DLBCLs regardless of subtype. Most DLBCLs arise from B cells transiting the germinal center reaction during 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 T follicular helper (THF cells). During their proliferative 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 distinct 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. Keywords: genomics, epigenomics, and other -omics, tumor biology and heterogeneity No conflicts of interests pertinent to the abstract.
Source: Hematological Oncology
DOI: 10.1002/hon.3163_50
Author: A. M. Melnick
Institution: Weill Cornell Medicine
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Amgen, Bristol-Myers Squibb, Pfizer, AstraZeneca, Gilead Sciences, Fred Hutchinson Cancer Research Center, Celgene, Vanda Pharmaceuticals, BeiGene, Incyte, Seagen, Coherus Biosciences, Servier, MorphoSys, Genentech, Merck Sharp and Dohme, Kite Pharma, Juno Therapeutics, Ignyta, Legend Biotech
OpenAlex ID: W4380079156