CD30, first described as the Ki antigen on malignant B cells in Hodgkin's lymphoma, is also expressed on normal activated B and T cells. It can be cleaved from the cell surface and detected in normal serum as soluble CD30 (sCD30), where it can be an indicator of levels of immune activation. In a cross-sectional study utilizing archived sera at a time point close to but preceding a diagnosis of acquired immunodeficiency syndrome (AIDS)-associated non-Hodgkin's B cell lymphoma, AIDS lymphoma subjects (n = 49) showed elevated mean levels of sCD30 compared to controls with AIDS but no malignancy (n = 44, p < 0.01), HIV-infected but relatively healthy (n = 47, p < 0.001), or HIV-seronegative controls (n = 44, p < 0.001). Serum sCD30 was significantly correlated to serum levels of the B cell cytokines interleukin-6 (IL-6), IL-10, and sCD23, but only among lymphoma subjects (p < or = 0.05). Correlations between sCD30 and other markers of immune system activation were seen among all HIV-infected subjects (sCD27, sCD44, CXCL13, p < 0.05). These observations suggest that sCD30, especially in combination with other immune system molecules, could be an important biomarker for an immune system environment conducive to B cell hyperactivation and the development of AIDS-associated B cell lymphoma.
"Chronic B cell activation may drive proliferation of antigen-selected B cell clones that accumulate genetic lesions and ultimately undergo neoplastic transformation. Indeed, elevated serum levels of several B cell stimulatory factors, including cytokines  and other soluble proteins [7-9], occur before the diagnosis of AIDS-associated lymphoma. In addition, continued antigenic stimulation of B cells by HIV [10-12] or other infectious agents such as Epstein-Barr virus  or human herpesvirus 8 (HHV-8)  seems to be critical for lymphomagenesis. "
[Show abstract][Hide abstract] ABSTRACT: Human Immunodeficiency Virus Type I (HIV-1) infection is associated with a high incidence of B-cell lymphomas. The role of HIV in these lymphomas is unclear and currently there are no valid in vivo models for better understanding HIV-related lymphomagenesis. Transgenic (Tg) 26 mice have a 7.4-kb pNL4-3 HIV-1 provirus lacking a 3.1-kb sequence encompassing parts of the gag-pol region. Approximately 15% of these HIV Tg mice spontaneously develop lymphoma with hallmark pre-diagnostic markers including skin lesions, diffuse lymphadenopathy and an increase in pro-inflammatory serum cytokines. Here we describe the phenotypic and molecular characteristics of the B cell leukemia/lymphoma in the Tg mice.
The transformed B cell population consists of CD19+pre-BCR+CD127+CD43+CD93+ precursor B cells. The tumor cells are clonal and characterized by an increased expression of several cellular oncogenes. Expression of B cell-stimulatory cytokines IL-1beta, IL-6, IL-10, IL-12p40, IL-13 and TNFalpha and HIV proteins p17, gp120 and nef were elevated in the Tg mice with lymphoma.
Increased expression of HIV proteins and the B-cell stimulatory factors is consistent with the interpretation that one or more of these factors play a role in lymphoma development. The lymphomas share many similarities with those occurring in HIV/AIDS+ patients and may provide a valuable model for understanding AIDS-related lymphomagenesis and elucidating the role played by HIV-1.
"HIV also causes an inflammatory milieu which further drives the activation and proliferation of B lymphocytes . Specifically levels of soluble CD30 have been noted to be elevated prior to diagnosis of NHL in HIV patients . Other cytokines have also been implicated in this process, notably IL-6, IL-10, and TNF-α [27, 28] (Figure 1). "
[Show abstract][Hide abstract] ABSTRACT: Immune surveillance is a dynamic process that involves an intact immune system to identify and protect the host against tumor development. The increased understanding of the genetics, infections and hematological malignancies in congenital immune deficiency states supports the concept that impaired T cells and Natural-killer/T cells leads to B-cell lymphoma. Furthermore, severe combined immunodeficient mice are prone to spontaneous tumor development and therefore serve as experimental models. Here we discuss the acquired conditions and mechanisms involved in dysregulation of the immune system that lead to lymphoma. Preemptive strategies to improve immune regulation and response and restore a competent immune system may lead to a decrease in lymphoid malignancies.
American Journal of Blood Research 05/2013; 3(2):91-101.
"In our experiments, vorinostat modulated the expression of cell cycle, apoptosis, and differentiation genes known to be altered in haematologic malignancies, increasing expression of those genes normally down-regulated in MDS and/or AML and suppressing genes normally over-expressed in these malignancies (Figures 4, 5, 6). Vorinostat up-regulated the expression of genes involved in cell signalling (cFOS, RAI3) , , cell cycle arrest (p15, p21, Cyclin G2) , , , cell cycle checkpoint and DNA repair (RAD9A) , cell differentiation (NOTCH2)  and down-regulated the expression levels of important genes involved in cell cycle transition (Cyclin D1, CUL1) , , , double strand break repair (NBN), cell proliferation and survival (c-MYC, AXL, MZF1, STAT5A, NFκB1, TNFRSF8) , , , , , , . Pro-apoptotic genes (e.g. "
[Show abstract][Hide abstract] ABSTRACT: Aberrant epigenetic patterns are central in the pathogenesis of haematopoietic diseases such as myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Vorinostat is a HDACi which has produced responses in these disorders. The purpose of this study was to address the functional effects of vorinostat in leukemic cell lines and primary AML and MDS myeloid cells and to dissect the genetic and molecular mechanisms by which it exerts its action.
Functional assays showed vorinostat promoted cell cycle arrest, inhibited growth, and induced apoptosis and differentiation of K562, HL60 and THP-1 and of CD33(+) cells from AML and MDS patients. To explore the genetic mechanism for these effects, we quantified gene expression modulation by vorinostat in these cells. Vorinostat increased expression of genes down-regulated in MDS and/or AML (cFOS, COX2, IER3, p15, RAI3) and suppressed expression of genes over-expressed in these malignancies (AXL, c-MYC, Cyclin D1) and modulated cell cycle and apoptosis genes in a manner which would favor cell cycle arrest, differentiation, and apoptosis of neoplastic cells, consistent with the functional assays. Reporter assays showed transcriptional effect of vorinostat on some of these genes was mediated by proximal promoter elements in GC-rich regions. Vorinostat-modulated expression of some genes was potentiated by mithramycin A, a compound that interferes with SP1 binding to GC-rich DNA sequences, and siRNA-mediated SP1 reduction. ChIP assays revealed vorinostat inhibited DNA binding of SP1 to the proximal promoter regions of these genes. These results suggest vorinostat transcriptional action in some genes is regulated by proximal promoter GC-rich DNA sequences and by SP1.
This study sheds light on the effects of vorinostat in AML and MDS and supports the implementation of clinical trials to explore the use of vorinostat in the treatment of these diseases.
PLoS ONE 01/2013; 8(1):e53766. DOI:10.1371/journal.pone.0053766 · 3.23 Impact Factor
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