Transcriptional signature with differential expression of BCL6 target genes accurately identifies BCL6-dependent diffuse large B cell lymphomas

Jose M. Polo, Przemyslaw Juszczynski, Stefano Monti, Leandro Cerchietti, Qian K. Ye, John M. Greally, Margaret Shipp, Ari Melnick

Research output: Contribution to journalArticle

99 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3207-3212
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number9
DOIs
StatePublished - Feb 27 2007

Fingerprint

Lymphoma, Large B-Cell, Diffuse
Genes
Germinal Center
Transcriptome
Neoplasms
Cell Cycle Proteins
Genetic Translocation
Ubiquitination
DNA Damage
Chromatin
Transcription Factors
Genome
Cell Line

Keywords

  • ChIP on ChIP
  • Gene expression profiling
  • Integrative analysis
  • Targeted therapy
  • Transcriptional repression

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Transcriptional signature with differential expression of BCL6 target genes accurately identifies BCL6-dependent diffuse large B cell lymphomas. / Polo, Jose M.; Juszczynski, Przemyslaw; Monti, Stefano; Cerchietti, Leandro; Ye, Qian K.; Greally, John M.; Shipp, Margaret; Melnick, Ari.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 9, 27.02.2007, p. 3207-3212.

Research output: Contribution to journalArticle

@article{870fdc8c764744f09036cbfb5026ab67,
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.",
keywords = "ChIP on ChIP, Gene expression profiling, Integrative analysis, Targeted therapy, Transcriptional repression",
author = "Polo, {Jose M.} and Przemyslaw Juszczynski and Stefano Monti and Leandro Cerchietti and Ye, {Qian K.} and Greally, {John M.} and Margaret Shipp and Ari Melnick",
year = "2007",
month = "2",
day = "27",
doi = "10.1073/pnas.0611399104",
language = "English (US)",
volume = "104",
pages = "3207--3212",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "9",

}

TY - JOUR

T1 - Transcriptional signature with differential expression of BCL6 target genes accurately identifies BCL6-dependent diffuse large B cell lymphomas

AU - Polo, Jose M.

AU - Juszczynski, Przemyslaw

AU - Monti, Stefano

AU - Cerchietti, Leandro

AU - Ye, Qian K.

AU - Greally, John M.

AU - Shipp, Margaret

AU - Melnick, Ari

PY - 2007/2/27

Y1 - 2007/2/27

N2 - 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.

AB - 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.

KW - ChIP on ChIP

KW - Gene expression profiling

KW - Integrative analysis

KW - Targeted therapy

KW - Transcriptional repression

UR - http://www.scopus.com/inward/record.url?scp=33847674920&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847674920&partnerID=8YFLogxK

U2 - 10.1073/pnas.0611399104

DO - 10.1073/pnas.0611399104

M3 - Article

VL - 104

SP - 3207

EP - 3212

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 9

ER -