Kaposi's sarcoma-associated herpesvirus-infected primary effusion lymphoma has a plasma cell gene expression profile - PubMed (original) (raw)
Kaposi's sarcoma-associated herpesvirus-infected primary effusion lymphoma has a plasma cell gene expression profile
Richard G Jenner et al. Proc Natl Acad Sci U S A. 2003.
Abstract
Kaposi's sarcoma-associated herpesvirus is associated with three human tumors: Kaposi's sarcoma, and the B cell lymphomas, plasmablastic lymphoma associated with multicentric Castleman's disease, and primary effusion lymphoma (PEL). Epstein-Barr virus, the closest human relative of Kaposi's sarcoma-associated herpesvirus, mimics host B cell signaling pathways to direct B cell development toward a memory B cell phenotype. Epstein-Barr virus-associated B cell tumors are presumed to arise as a consequence of this virus-mediated B cell activation. The stage of B cell development represented by PEL, how this stage relates to tumor pathology, and how this information may be used to treat the disease are largely unknown. In this study we used gene expression profiling to order a range of B cell tumors by stage of development. PEL gene expression closely resembles that of malignant plasma cells, including the low expression of mature B cell genes. The unfolded protein response is partially activated in PEL, but is fully activated in plasma cell tumors, linking endoplasmic reticulum stress to plasma cell development through XBP-1. PEL cells can be defined by the overexpression of genes involved in inflammation, cell adhesion, and invasion, which may be responsible for their presentation in body cavities. Similar to malignant plasma cells, all PEL samples tested express the vitamin D receptor and are sensitive to the vitamin D analogue drug EB 1089 (Seocalcitol).
Figures
Fig. 1.
Assembly of B cell tumors according to developmental stage by gene expression profiling. (A) Hierarchical clustering of filtered data (1,842 genes) from 38 arrays, hybridized with the samples named. Technical replicates, which are red, and biological replicates, which are blue, always cluster together. The dendogram relates samples by their gene expression pattern, with short branch lengths indicating similarity. The red and blue horizontal lines show the limit of technical and biological variation, respectively. (B) Hierarchical clustering of 26 samples and a filtered set of 1,987 genes. Each column represents one sample and each row one gene. Gene expression is shown as a pseudocolored representation of log2 expression ratio with red being above and green being below the row/column median level of expression as shown by the scale. Gray indicates data removed by filtering. Samples cluster by the tumor type from which they were derived: pink, acute lymphoblastic leukemia (ALL); dark blue, GC-like DLBCL and FL; light blue, BL; dark green, CLL and HCL; light green, HL and anaplastic DLBCL; orange, PEL; red, MM, PCL, and DS-1, which was derived from immunoblastic lymphoma. The ordering of the samples, which was determined by a one-dimensional self-organizing map, mirrors the order of their known normal B cell counterparts in B cell development (indicated by the arrow and names above). The colored bars to the right mark gene expression signatures, which vary in expression across the dataset. The bar labeled PEL indicates genes expressed strongly in PEL.
Fig. 2.
Activation of the unfolded protein response in PEL and plasma cell tumors. (A) Detail of the ER and UPR cluster (Fig. 1_B_), which has the highest expression in plasma cell derived tumors (red), and is also increased in PEL cells (orange). The Human Genome Organisation (HUGO) gene identifiers and gene names are indicated to the right of each row. Genes whose products have a role in ER or Golgi function or vesicle trafficking are named in red. Genes marked by asterisks (*) are discussed in the text. (B) Expression of ATF6 protein measured by Western blotting. The positions of molecular weight markers are shown on the left. The active 50-kDa form of ATF6, which induces the UPR, is expressed strongly in the anaplastic DLBCL-derived cell line DEL, PEL cells, and MM-derived cell lines. Except for a small number of cases, protein levels correlate with ATF6 and S1P mRNA expression measured by using microarrays (shown below).
Fig. 3.
Identification of genes that define PEL. The 75 genes most associated with PEL by using a Mann-Whitney U test (P values from 2.91 × 10-7 to 1.36 × 10-4). Each column represents one sample, and each row represents one gene (identified by HUGO ID and gene name). The majority of genes can be classified by their involvement in either inflammation, adhesion, and invasion (blue) or ER, Golgi, and vesicle trafficking (red).
Fig. 4.
PEL is sensitive to the vitamin D analogue drug EB 1089 (Seocalcitol). (A) Expression of the VDR measured by Western blotting. The receptor is strongly expressed in PEL cells. Protein levels correlate with VDR mRNA expression measured by using microarrays (shown below). (B) In vitro [3H]thymidine incorporation of cell lines and primary tumor cells as percentage of no drug control after addition of EB 1089 at concentrations increasing at half-log10 intervals from 0.1 to 100 nM (means and SD shown, n = 3). Sensitivity to EB 1089 and expression of VDR are scored underneath.
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