We previously identified novel human ets-1 transcripts in which the normal order of exons is inverted, and demonstrated that although the order of exons is different than in the genomic DNA, splicing of these exons out of order occurs in pairs using genuine splice sites (1). Here we determine the structure of these novel transcripts, showing that they correspond to circular RNA molecules containing only exons in genomic order. These transcripts are stable molecules, localized in the cytoplasmic component of the cells. To our knowledge, this is the first case of circular transcripts being processed from nuclear pre-mRNA in eukaryotes. This new type of transcript might represent a novel aspect of gene expression and hold some interesting clues about the splicing mechanism.

Multiple myeloma (MM) cells inhibit certain T-cell functions. We examined the expression of B7-H1 (PD-L1), a B7-related protein that inhibits T-cell responses, in CD138- IntroductionIn addition to the cytogenic and molecular abnormalities reportedly associated with malignant transformation of plasma cells, interactions between multiple myeloma (MM) cells and the bone marrow microenvironment are crucial for plasma cell survival and proliferation. [1][2][3] Several factors that mediate MM cell cross-talk with mesenchymalderived cells, such as vascular endothelial growth factor, an angiogenic factor, have been previously described; however, there is growing evidence that MM cells also interact with immune cells. Plasma cells interact with T cells via the RANK/RANK-L system. 4 A recent study demonstrated that the survival and growth of malignant plasma cells was supported by bone marrow dendritic cells via RANK/RANK-L and BAFF-APRIL. 5 There is also evidence that malignant plasma cells can be targeted for an immune response. Several tumor antigens are expressed by plasma cells isolated from MM and monoclonal gammopathy of undetermined significance (MGUS) patients, and allogenic bone marrow transplantation can induce a graft-versus-myeloma effect. [6][7][8] However, MM is also associated with immune dysfunction. Defects in T-cell responses to mitogenic and TCR-mediated stimulation have been reported. [9][10][11] Interestingly, regulatory T cell (T reg cell) populations are significantly modified in both MGUS and MM patients, suggesting that immune dysfunction is an early event in the malignant transformation process of plasma cells. 12,13 However, the factors produced by plasma cells that create these immune defects are poorly defined.A possible candidate responsible for such T-cell inhibitory mechanisms in MM plasma cells is B7-H1. B7-H1 (also known as PD-L1 or CD274) is a B7 family member and is the ligand for PD-1 (programmed death-1), a member of the CD28 family. 14 B7-H1 is broadly distributed in various tissues and cell types and is often expressed after exposure to inflammatory cytokines, especially IFN-␥. B7-H1 interacts with PD-1 and another as yet unknown receptor on T cells and can inhibit T cell activation and cytotoxic T lymphocytes (CTL)-mediated lysis. [15][16][17][18] B7-H1 can also increase T-cell activation. [19][20][21] Marked expression of B7-H1 has been reported for various human carcinomas and in mouse models expression of B7-H1 enhances tumor growth and allows dormant tumor cells to escape from CTLs. 16,[22][23][24][25][26][27][28][29] Blocking B7-H1 enhances the effects of cancer vaccines. [30][31][32][33][34] Toll-like receptor (TLR) stimulation can also induce B7-H1 expression in mouse tumor cells. 35 Thus, B7-H1 overexpression appears as a possible mechanism for tumors to avoid the host's immune response.Little is known regarding the expression of B7-H1 in B-lineage lymphocytes. We show here that B7-H1 is expressed by malignant plasma cells from most MM patients but not from MGUS patients. ...