Unique and Shared Epigenetic Programs of the CREBBP and EP300 Acetyltransferases in Germinal Center B Cells Reveal Targetable Dependencies in Lymphoma

• Published in: Immunity (Cambridge, Mass.) Vol. 51; no. 3; pp. 535 - 547.e9
• Main Authors: Meyer, Stefanie N., Scuoppo, Claudio, Vlasevska, Sofija, Bal, Elodie, Holmes, Antony B., Holloman, Mara, Garcia-Ibanez, Laura, Nataraj, Sarah, Duval, Romain, Vantrimpont, Thomas, Basso, Katia, Brooks, Nigel, Dalla-Favera, Riccardo, Pasqualucci, Laura
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.09.2019; Elsevier Limited
• Subjects: acetyltransferase inhibitor; Acetyltransferases - genetics; Animal models; Animals; B-cell lymphoma; B-Lymphocytes - physiology; Cell Line; Clonal deletion; CREB-Binding Protein - genetics; CREBBP; dark zone; diffuse large cell lymphoma; E1A-Associated p300 Protein - genetics; Enzymes; EP300; Epigenesis, Genetic - genetics; Fitness; Genomes; Genomics; germinal center; Germinal Center - physiology; Germinal centers; HEK293 Cells; Humans; Inhibitors; light zone; Lymphocytes B; Lymphoma; Lymphoma, Follicular - etiology; Lymphoma, Large B-Cell, Diffuse - genetics; Mice; Mice, Inbred C57BL; Mutation; Reproductive fitness; Sequence Deletion - genetics; Software; synthetic lethality; Transcription; Transcription, Genetic - genetics; dark zone; diffuse large cell lymphoma; CREBBP; acetyltransferase inhibitor; synthetic lethality; EP300; light zone; germinal center
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2019.08.006

Inactivating mutations of the CREBBP and EP300 acetyltransferases are among the most common genetic alterations in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Here, we examined the relationship between these two enzymes in germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and in lymphomagenesis by using conditional GC-directed deletion mouse models targeting Crebbp or Ep300. We found that CREBBP and EP300 modulate common as well as distinct transcriptional programs implicated in separate anatomic and functional GC compartments. Consistently, deletion of Ep300 but not Crebbp impaired the fitness of GC B cells in vivo. Combined loss of Crebbp and Ep300 completely abrogated GC formation, suggesting that these proteins partially compensate for each other through common transcriptional targets. This synthetic lethal interaction was retained in CREBBP-mutant DLBCL cells and could be pharmacologically targeted with selective small molecule inhibitors of CREBBP and EP300 function. These data provide proof-of-principle for the clinical development of EP300-specific inhibitors in FL and DLBCL. [Display omitted] •CREBBP and EP300 control distinct as well as shared transcriptional targets in the GC•Deletion of Crebbp and Ep300 in B cells abrogates GC formation, revealing paralog lethality•CREBBP-mutant DLBCL cells are preferentially sensitive to EP300 deletion•EP300-dependency can be pharmacologically targeted by CREBBP and EP300 inhibitors Loss-of-function mutations of CREBBP and EP300 are frequent and early events in the pathogenesis of FL and DLBCL, the two most common lymphoma subtypes. Meyer et al. uncover distinct as well as compensatory roles for these acetyltransferases in separate compartments of the germinal center and exploit this notion to document an EP300-dependency in CREBBP-deficient lymphoma cells that can be targeted therapeutically.