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.targeted therapy ͉ transcriptional repression ͉ ChIP on ChIP ͉ integrative analysis ͉ gene expression profiling B CL6 is a BTB/POZ domain transcription repressor that is required for normal germinal center (GC) development and expressed by the majority of normal GC B cells and a subset of diffuse large B cell lymphomas (DLBCLs) (1, 2). BCL6 favors the survival and proliferation of GC B cells, which undergo somatic hypermutation of Ig variable regions and Ig class switch recombination; down-regulation of BCL6 is necessary for post-GC B cell maturation (3-5). Deregulation of BCL6, by chromosomal translocation or aberrant somatic hypermutation, is the most common genetic abnormality in DLBCL (6). Conclusive evidence for the oncogenic role of BCL6 comes from murine models in which constitutive BCL6 expression results in the development of a lymphoid malignancy resembling DLBCL (7,8). Although deregulated BCL6 clearly plays a pathogenetic role in a subset of human DLBCLs, other DLBCLs may simply express this transcriptional repressor because the lymphomas are derived from normal BCL6 ϩ GC B cells. Identification of BCL6-dependent tumors has important therapeutic implications because a recently described specific BCL6 peptide inhibitor (BPI) inhibits the growth of some but not all DLBCLs (9).To delineate functionally relevant DLBCL subsets, we and others have used gene expression signatures. In an earlier approach known as the cell of origin (COO) classification, subsets of DLBCLs were associated with specific types of normal B cells [GC B cells (GCB) or in vitro activated peripheral blood B cells (ABC)] or left unassigned if ...

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

“…1D). This indicates a role for Bcl6 in the maintenance of BCR signaling, which is in line with previous reports [19,27,37,38]. In accordance with the non-signaling and IgM-secreting phenotype, the knockout cells had reduced surface IgM expression (Fig.…”

Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas

“…The frequent 53BP1 copy loss in BCR DLBCLs suggests that aberrant DNA-damage responses may play a particularly important role in these tumors, potentially in association with programmed DNA breaks of the immunoglobulin locus. As noted, BCR DLBCLs are uniquely reliant upon BCL6 (Polo et al, 2007), a transcription repressor which targets p53 and inactivates the p53-independent DNA-damage response pathway via Miz-1-dependent transcriptional repression of CDKN1A (Phan and Dalla-Favera, 2004;Phan et al, 2005;Wu and Jelinek, 2005). In normal and malignant GC B cells, BCL6 likely limits the p53-dependent and p53-independent DNA-damage responses associated with somatic hypermutation and CSR (Phan and Dalla-Favera, 2004;Phan et al, 2005;Wu and Jelinek, 2005).…”

“…In contrast, BCR DLBCLs express higher levels of multiple BCR signaling cascade components, DNAdamage response proteins such as H2AX and B-cell transcription factors including BCL6; these tumors also have more frequent BCL6 translocations (Monti et al, 2005;Takahashi et al, 2006). Recent studies also indicate that BCR DLBCLs exhibit unique reliance upon BCL6 signaling and sensitivity to BCL6 peptide inhibitors (Polo et al, 2007).…”

ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes

“…Thus, ChIP 2 data analysis methods often use highly conservative approaches aimed at minimizing the rate of false-positive predictions. Although several studies have experimentally validated novel target collections produced at a given statistical threshold (8)(9)(10)(11)(12), these studies likely miss a large number of true binding events, obscuring the full complexity of transcriptional processes.…”