Molecular pathogenesis of chronic lymphocytic leukemia: factors and signaling pathways regulating cell growth and survival.

Chronic lymphocytic leukemia is a malignant disease characterized by clonal expansion of relatively mature B-lymphocytes with a high percentage of cells arrested in the nonproliferative G0/G1 cell cycle phase. Possibly reflecting the clinical heterogeneity observed in patients, various signaling pathways may become affected during the initiation and course of this disease. This review discusses frequent alterations concerning proliferative, differentiation-inducing, and apoptotic pathways elucidated in the recent years that have improved our understanding of this disease.

Pyoderma gangrenosum associated with the secondary antiphospholipid syndrome.

A 64-year-old woman with an 11-year history of systemic lupus erythematosus and amputation of her left lower leg as a consequence of arterial embolism, presented with two large, non-healing ulcers on her right shank. Pyoderma gangrenosum associated with secondary antiphospholipid syndrome was diagnosed based upon the typical clinical features and increased antibodies to cardiolipin. Although an aggressive therapy with corticosteroids and cyclosporine was started, her condition continued to worsen.

Recombinant adeno-associated virus for the generation of autologous, gene-modified tumor vaccines: evidence for a high transduction efficiency into primary epithelial cancer cells.

To explore the potential of recombinant vectors based on recombinant adeno-associated virus (rAAV) for cancer vaccination, we investigated the transduction efficiency of rAAV into cancer cells ex vivo. Infection of human epithelial cancer cell lines with rAAV carrying reporter genes encoding beta-galactosidase (rAAV/LacZ) or luciferase (rAAV/Luc) resulted in high levels of reporter gene expression (>90% positive cells). In marked contrast, rAAV poorly transduced all murine tumor cell lines, as well as human hematopoietic cell lines.

Gene transfer of the costimulatory molecules B7-1 and B7-2 into human multiple myeloma cells by recombinant adeno-associated virus enhances the cytolytic T cell response.

Gene transfer of the costimulatory molecules B7-1 and B7-2 induces a potent antitumor immune response in a variety of tumor models. B cell neoplasms including multiple myeloma (MM) often show little or no expression of B7 antigens; they are therefore a potential target for this approach. To increase the expression of human B7 genes in MM cells, both genes and the neomycin phosphotransferase gene were packaged into recombinant adeno-associated virus vectors (rAAV).

Recombinant adeno-associated virus (rAAV) vectors for somatic gene therapy: recent advances and potential clinical applications.

Adeno-associated virus (AAV) is a single-stranded DNA dependovirus of the family of Parvoviridae that has promising features as a vector for somatic gene therapy. Different recombinant (r) AAV vectors have been generated that seem to have some advantages compared with other vector systems, such as the transduction of terminally differentiated and non-dividing cells, the lack of any apparent pathogenicity, low immunogenicity, relatively high stability of transgene expression, and the potential of targeted integration. Recent improvements in rAAV packaging should allow the generation of sufficient quantities of rAAV for clinical trials.

High-efficiency transfer of the T cell co-stimulatory molecule B7-2 to lymphoid cells using high-titer recombinant adeno-associated virus vectors.

Adeno-associated virus (AAV) is a single-stranded DNA virus that can either integrate or replicate in host cells. Production of recombinant viral particles (rAAV) requires expression of the viral structural genes and the viral inverted terminal repeats in cis. By using an SV40 replicon to amplify the structural genes, the yield of recombinant viral particles was increased 60-fold over a nonreplicating helper plasmid.

CD30 ligand signal transduction involves activation of a tyrosine kinase and of mitogen-activated protein kinase in a Hodgkin's lymphoma cell line.

CD30 is a transmembrane receptor of the nerve growth factor/tumor necrosis factor receptor superfamily. Its expression associated with Hodgkin's lymphoma and a subset of non-Hodgkin's lymphoma. Recently, its ligand (CD30L) has been cloned.

Proposed interaction between insulin and retinoblastoma protein.

Retinoblastoma protein (RB) is a tumor suppressor gene product involved in embryogenesis and cell cycle progression. One of the major mechanisms leading to RB dysfunction is complex formation with viral oncoproteins using the common RB binding motif Leu X Cys X Glu (LXCXE) which has also been identified in cellular ligands, e.g.

Prediction of homologous binding sites on RB and p107 common for viral oncoproteins and cellular ligands.

Hydropathic anticomplementarity of amino acids specifies that peptides translated from complementary DNA strands may acquire amphiphilic conformations and bind to each other. This concept has been coined 'Molecular Recognition Theory' (MRT) or 'complementary peptide theory'. Inactivation of retinoblastoma protein (RB), a tumor suppressor gene product, has been shown to be involved in the pathogenesis of many tumors and to be due to either mutation of the RB gene, hyperphosphorylation or complex formation with viral oncoproteins.

Single-cell detection of ets-1 transcripts in human neuroectodermal cells.

The genes of the ets family are thought to code for a novel class of transcriptional factors. These proteins have a specific DNA-binding domain different from the basic domain of both the helix-loop-helix and leucine zipper families of DNA-binding proteins. The ets-1 gene product has been shown to bind to the enhancer region of the human T-cell receptor alpha gene during thymocyte ontogeny.