TitleTranscriptional signature with differential expression of BCL6 target genes accurately identifies BCL6-dependent diffuse large B cell lymphomas.
Publication TypeJournal Article
Year of Publication2007
AuthorsPolo, Jose M., Juszczynski Przemyslaw, Monti Stefano, Cerchietti Leandro, Ye Kenny, Greally John M., Shipp Margaret, and Melnick Ari
JournalProc Natl Acad Sci U S A
Date Published2007 Feb 27
KeywordsCell Line, Tumor, Chromatin Immunoprecipitation, DNA-Binding Proteins, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, Humans, Lymphoma, Large B-Cell, Diffuse, Peptides, Proto-Oncogene Proteins c-bcl-6, Signal Transduction, Transcription, Genetic

<p>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.</p>

Alternate JournalProc Natl Acad Sci U S A
PubMed ID17360630
PubMed Central IDPMC1805543
Grant ListP01 CA092625 / CA / NCI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States
P01CA092625 / CA / NCI NIH HHS / United States