title: Transcriptional signature with differential expression of BCL6 target genes accurately identifies BCL6-dependent diffuse large B cell lymphomas.
abstract: Diffuse large B cell lymphomas (DLBCLs) often express BCL6, a transcriptional repressor required for the formation of normal germinal centers. In a subset of DLBCLs, BCL6 is deregulated by chromosomal translocations or aberrant somatic hypermutation; in other tumors, BCL6 expression may simply reflect germinal center lineage. DLBCLs dependent on BCL6-regulated pathways should exhibit differential regulation of BCL6 target genes. Genomic array ChIP-on-chip was used to identify the cohort of direct BCL6 target genes. This set of genes was enriched in modulators of transcription, chromatin structure, protein ubiquitylation, cell cycle, and DNA damage responses. In primary DLBCLs classified on the basis of gene expression profiles, these BCL6 target genes were clearly differentially regulated in "BCR" tumors, a subset of DLBCLs with increased BCL6 expression and more frequent BCL6 translocations. In a panel of DLBCL cell lines analyzed by expression arrays and classified according to their gene expression profiles, only BCR tumors were highly sensitive to the BCL6 peptide inhibitor, BPI. These studies identify a discrete subset of DLBCLs that are reliant on BCL6 signaling and uniquely sensitive to BCL6 inhibitors. More broadly, these data show how genome-wide identification of direct target genes can identify tumors dependent on oncogenic transcription factors and amenable to targeted therapeutics.
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Polo
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Juszczynski
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: Kenny
authors.initials: K
authors.lastname: Ye
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
authors.forename: Margaret
authors.initials: M
authors.lastname: Shipp
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
mesh_terms: D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005796:Genes / Q000235:genetics*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D010455:Peptides / Q000494:pharmacology; D051560:Proto-Oncogene Proteins c-bcl-6; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D010455:Peptides; D051560:Proto-Oncogene Proteins c-bcl-6