Infection with SIVmac251 in some rhesus monkeys (Macaca mulatta) leads to B-cell non-Hodgkin's lymphomas (B-NHL) clinically similar to that of HIV-infected AIDS patients. To further characterize the SIV-associated B-NHL we have generated genetic profiles of malignant cells by subtractive hybridization and Northern blot analysis. We have analyzed 21 clones of a subtracted cDNA library corresponding to overexpressed genes in diffuse large B-cell (DLBCL) SIV-associated monkey lymphoma. Eight of these clones represent a sequence homologous to an abundant transcript from KG-1 cells originally established from a human myelogenous leukemia. The protein encoded has a 60% similarity to a hypothetical glycine-rich transmembrane signal protein of Caenorhabditis elegans and 25% similarity to the ret finger protein. The other cDNA clones contained sequences of the serum amyloid A gene (SAA), the alpha₁-acid glycoprotein gene (AGP), the ribosomal protein S3a (RPS3a) and L8 (RPL8) genes, the interferon-inducible gene (INF-ind), the metastasin gene (mts1), and the NADH dehydrogenase I gene (ND-I). The remaining cDNA clones consisted of yet unknown sequences. In addition, we detected an up-regulation of the cytochrome c oxidase II gene (COX-II), the ND-IV gene, and the SET oncogene by Northern blot hybridization in three SIV-associated NHLs of different histomorphological classification. All these genes have not previously been found to be overexpressed in B-NHL.

Several novel, differentially transcribed genes were identified in one centroblastic and one immunoblastic HIV-associated B-cell non-Hodgkin's lymphoma (B-NHL) by subtractive cloning. In both lymphomas, we detected an upregulated transcription of several mitochondrial genes. In the centroblastic B-NHL, we found a high level transcription of nuclear genes including the interferon-inducible gene (INF-ind), the immunoglobulin light chain gene (IgL), the set oncogene, and several unknown genes. The data obtained on upregulated expression of the genes in human B-NHL of HIV-infected patients considerably overlap with those obtained earlier for the B-NHL of simian immunodeficiency virus-infected monkeys. In the centroblastic lymphoma, one transcript revealed a fusion of the 3'-untranslated region of the set gene and the C-terminal region of the IgL gene. This chimeric sequence was confirmed by a site-directed polymerase chain reaction performed with total cDNA and genomic DNA. The expected amplification product was obtained in both cases pointing to a genomic rearrangement. The IgL-set fusion sequence was not found in cDNA preparations and genomic DNA of the immunoblastic HIV-associated B-NHL. Further studies are necessary to determine whether these genes contribute to lymphoma development or can be used as therapeutic targets.

DNA polymerase iota (Polι) of mammals is a member of the Y family of DNA polymerases. Among many other genome caretakers, these enzymes are responsible for maintaining genome stability. The members...

Parkinson’s disease (PD) is the second most common neurodegenerative diseases characterized by progressive loss of midbrain dopaminergic neurons in the substantia nigra. Mutations in the PARK2 gene are a frequent cause of familial forms of PD. Sustained chronic neuroinflammation in the central nervous system makes a significant contribution to neurodegeneration events. In response to inflammatory factors produced by activated microglia, astrocytes change their transcriptional programs and secretion profiles, thus acting as immunocompetent cells. Here, we investigated iPSC-derived glial cell cultures obtained from healthy donors (HD) and from PD patients with PARK2 mutations in resting state and upon stimulation by TNFα. The non-stimulated glia of PD patients demonstrated higher IL1B and IL6 expression levels and increased IL6 protein synthesis, while BDNF and GDNF expression was down-regulated when compared to that of the glial cells of HDs. In the presence of TNFα, all of the glial cultures displayed a multiplied expression of genes encoding inflammatory cytokines: TNFA, IL1B, and IL6, as well as IL6 protein synthesis, although PD glia responded to TNFα stimulation less strongly than HD glia. Our results demonstrated a pro-inflammatory shift, a suppression of the neuroprotective gene program, and some depletion of reactivity to TNFα in PARK2-deficient glia compared to glial cells of HDs.

Manganese (Mn) is crucially important for vital activity of cells and has many biological functions. Nevertheless, high doses of Mn taken up by an organism over a long period may cause neurodegenerative diseases such as manganism and Parkinsonism. The molecular mechanisms of this Mn toxicity are still poorly studied. It is now believed that Mn-induced pathophysiological neural processes are multifaceted and affect several metabolic pathways. In particular, Mn ions might affect the processes of DNA replication and repair. To test this possibility, we obtained an SKOV-3 cell line resistant to the toxic action of Mn ions. We found that these cells are characterized by the activation of poly(ADP-ribose)polymerase, which leads to increased ability to repair DNA. Thus, the model used here supports the suggestion that at least one cause of Mn cytotoxicity might be disorders of the processes involved in DNA replication and repair.