Article

A library of gene expression signatures to illuminate normal and pathological lymphoid biology

Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Immunological Reviews (Impact Factor: 12.91). 05/2006; 210:67-85. DOI: 10.1111/j.0105-2896.2006.00373.x
Source: PubMed

ABSTRACT Genomics has provided a lever to pry open lymphoid cells and examine their regulatory biology. The large body of available gene expression data has also allowed us to define the of coordinately expressed genes, termed gene expression signatures, which characterize the states of cellular physiology that reflect cellular differentiation, activation of signaling pathways, and the action of transcription factors. Gene expression signatures that reflect the action of individual transcription factors can be defined by perturbing transcription factor function using RNA interference (RNAi), small-molecule inhibition, and dominant-negative approaches. We have used this methodology to define gene expression signatures of various transcription factors controlling B-cell differentiation and activation, including BCL-6, B lymphocyte-induced maturation protein-1 (Blimp-1), X-box binding protein-1 (XBP1), nuclear factor-kappaB (NF-kappaB), and c-myc. We have also curated a wide variety of gene expression signatures from the literature and assembled these into a signature database. Statistical methods can define whether any signature in this database is differentially expressed in independent biological samples, an approach we have used to gain mechanistic insights into the origin and clinical behavior of B-cell lymphomas. We also discuss the use of genomic-scale RNAi libraries to identify genes and pathways that may serve as therapeutic targets in B-cell malignancies.

Download full-text

Full-text

Available from: Lloyd T Lam, Aug 17, 2015
0 Followers
 · 
155 Views
  • Source
    • "In a further attempt to distill the essentials of Myc action, the binding and expression changes among a set of genes accepted as bona fide Myc targets were highlighted (Shaffer et al., 2006). This Myc-signature set (defined in human cells) is comprised of Myc-binding genes that tend to be highly expressed (Figure S3A) and whose abundance changes with perturbation of Myc levels in a variety of systems (Ji et al., 2011; Shaffer et al., 2006). Signature genes were highly enriched in the common sectors between the data sets. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The c-Myc HLH-bZIP protein has been implicated in physiological or pathological growth, proliferation, apoptosis, metabolism, and differentiation at the cellular, tissue, or organismal levels via regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc's targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated, the transcriptomes and the genome-wide distributions of Myc, RNA polymerase II, and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity, but is a nonlinear amplifier of expression, acting universally at active genes, except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature.
    Cell 09/2012; 151(1):68-79. DOI:10.1016/j.cell.2012.08.033 · 33.12 Impact Factor
  • Source
    • ". IRF4 Controls Essential Gene-Expression Programs in ABC DLBCL (A) IRF4 direct target genes grouped according to gene-expression signatures (Shaffer et al., 2006). Signatures with significant enrichment for IRF4 targets were grouped by function (Table S3A "
    [Show abstract] [Hide abstract]
    ABSTRACT: Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.
    Cancer cell 06/2012; 21(6):723-37. DOI:10.1016/j.ccr.2012.05.024 · 23.89 Impact Factor
  • Source
    • "However, the mechanisms leading to this up-regulation is poorly understood. Previous reports had highlighted a correlation between NS expression and the presence of the active Myc oncogene (Dave et al 2006, Rosenwald et al 2002, Shaffer et al 2006). In this manuscript we further extend such a correlation to a large panel of human cancer cell lines (NC60) and show dramatic accumulation of NS in Myc-driven Bcell lymphomas isolated from Eu-Myc mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nucleostemin (NS), a nucleolar GTPase, is highly expressed in stem/progenitor cells and in most cancer cells. However, little is known about the regulation of its expression. Here, we identify the NS gene as a novel direct transcriptional target of the c-Myc oncoprotein. We show that Myc overexpression enhances NS transcription in cultured cells and in pre-neoplastic B cells from Eμ-myc transgenic mice. Consistent with NS being downstream of Myc, NS expression parallels that of Myc in a large panel of human cancer cell lines. Using chromatin immunoprecipitation we show that c-Myc binds to a well-conserved E-box in the NS promoter. Critically, we show NS haploinsufficiency profoundly delays Myc-induced cancer formation in vivo. NS+/-Eμ-myc transgenic mice have much slower rates of B-cell lymphoma development, with life spans twice that of their wild-type littermates. Moreover, we demonstrate that NS is essential for the proliferation of Myc-overexpressing cells in cultured cells and in vivo: impaired lymphoma development was associated with a drastic decrease of c-Myc-induced proliferation of pre-tumoural B cells. Finally, we provide evidence that in cell culture NS controls cell proliferation independently of p53 and that NS haploinsufficiency significantly delays lymphomagenesis in p53-deficient mice. Together these data indicate that NS functions downstream of Myc as a rate-limiting regulator of cell proliferation and transformation, independently from its putative role within the p53 pathway. Targeting NS is therefore expected to compromise early tumour development irrespectively of the p53 status.
    Oncogene 11/2011; 31(28):3311-21. DOI:10.1038/onc.2011.507 · 8.56 Impact Factor
Show more