Epigenetically programmed identity crisis to combat diffuse large B cell lymphoma

Germinal center B cell-like diffuse large B cell lymphoma (GCB-DLBCL) originates from the malignant transformation of germinal center B cells. This process is driven by transcriptional and epigenetic dysregulations, frequently caused by recurrent mutations and chromosomal translocations. These changes lead to a differentiation arrest associated with unchecked proliferation and survival. This review highlights key transcriptional and epigenetic dependencies that sustain the GCB-DLBCL phenotype and identifies therapeutic vulnerabilities. Epigenetic targeting of these vulnerabilities unlocks tumor cells from their differentiation arrest, enabling further yet incomplete differentiation toward an antiproliferative, proapoptotic plasma cell-like or memory B cell-like state. We define this transition as an epigenetically programmed identity crisis, a promising therapeutic strategy to target GCB-DLBCL and potentially other malignancies.