Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is curable in less than 50% of patients. Prognostic models based on pre-treatment characteristics, such as the International Prognostic Index (IPI), are currently used to predict outcome in DLBCL. However, clinical outcome models identify neither the molecular basis of clinical heterogeneity, nor specific therapeutic targets. We analyzed the expression of 6,817 genes in diagnostic tumor specimens from DLBCL patients who received cyclophosphamide, adriamycin, vincristine and prednisone (CHOP)-based chemotherapy, and applied a supervised learning prediction method to identify cured versus fatal or refractory disease. The algorithm classified two categories of pa- tients with very different five-year overall survival rates (70% versus 12%). The model also ef- fectively delineated patients within specific IPI risk categories who were likely to be cured or to die of their disease. Genes implicated in DLBCL outcome included some that regulate responses to B-cell-receptor signaling, critical serine/threonine phosphorylation pathways and apoptosis. Our data indicate that supervised learning classification techniques can predict outcome in DLBCL and identify rational targets for intervention. © 2002 Nature Publishing Group http://medicine.nature.com

/pdf/diffuse-large-b-cell-lymphoma-outcome-prediction-by-gene-2dnd8dxnlx.pdf

Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning

This year marks the 25th anniversary of the first Annual Review of Immunology article to describe features of the T cell antigen receptor (TCR). In celebration of this anniversary, we begin with a brief introduction outlining the chronology of the earliest studies that established the basic paradigm for how the engaged TCR transduces its signals. This review continues with a description of the current state of our understanding of TCR signaling, as well as a summary of recent findings examining other key aspects of T cell activation, including cross talk between the TCR and integrins, the role of costimulatory molecules, and how signals may negatively regulate T cell function.

T cell activation.

NF-κB pathway consists of canonical and non-canonical pathways. The canonical NF-κB is activated by various stimuli, transducing a quick but transient transcriptional activity, to regulate the expression of various proinflammatory genes and also serve as the critical mediator for inflammatory response. Meanwhile, the activation of the non-canonical NF-κB pathway occurs through a handful of TNF receptor superfamily members. Since the activation of this pathway involves protein synthesis, the kinetics of non-canonical NF-κB activation is slow but persistent, in concordance with its biological functions in the development of immune cell and lymphoid organ, immune homeostasis and immune response. The activation of the canonical and non-canonical NF-κB pathway is tightly controlled, highlighting the vital roles of ubiquitination in these pathways. Emerging studies indicate that dysregulated NF-κB activity causes inflammation-related diseases as well as cancers, and NF-κB has been long proposed as the potential target for therapy of diseases. This review attempts to summarize our current knowledge and updates on the mechanisms of NF-κB pathway regulation and the potential therapeutic application of inhibition of NF-κB signaling in cancer and inflammatory diseases.

/pdf/targeting-nf-kb-pathway-for-the-therapy-of-diseases-rkkgu4xa4c.pdf

Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study.

Calcium signals in cells of the immune system participate in the regulation of cell differentiation, gene transcription and effector functions. An increase in intracellular levels of calcium ions (Ca2+) results from the engagement of immunoreceptors, such as the T-cell receptor, B-cell receptor and Fc receptors, as well as chemokine and co-stimulatory receptors. The major pathway that induces an increase in intracellular Ca2+ levels in lymphocytes is through store-operated calcium entry (SOCE) and calcium-release-activated calcium (CRAC) channels. This Review focuses on the role of Ca2+ signals in lymphocyte functions, the signalling pathways leading to Ca2+ influx, the function of the recently discovered regulators of Ca2+ influx (STIM and ORAI), and the relationship between Ca2+ signals and diseases of the immune system.

Calcium signalling in lymphocyte activation and disease.

The function of the Src-family kinases (SFKs) Lck and Fyn in T cells has been intensively studied over the past 15 years. Animal models and cell line studies both indicate a critical role for Lck and Fyn in proximal T-cell antigen receptor (TCR) signal transduction. Recruited SFKs phosphorylate TCR ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains, which then serve as docking sites for Syk-family kinases. SFKs then phosphorylate and activate the recruited Syk-family kinase. Lck and Fyn are spatially segregated in cell membranes due to differential lipid raft localization, and may undergo sequential activation. In addition to the CD4 and CD8 coreceptors, a recently described adaptor, Unc119, may link SFKs to the TCR. CD45 and Csk provide positive and negative regulatory control of SFK functions, respectively, and Csk is constitutively bound to the transmembrane adapter protein, PAG/Cbp. TCR-based signaling is required at several stages of T-cell development, including at least pre-TCR signaling, positive selection, peripheral maintenance of naive T cells, and lymphopenia-induced proliferation. SFKs are required for each of these TCR-based signals, and Lck seems to be the major contributor.

Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation.

Essential Role of LAT in T Cell Development

Recent data indicate that several members of the Tec family of protein tyrosine kinases function in antigen receptor signal transduction. Txk, a Tec family protein tyrosine kinase, is expressed in both immature and mature T cells and in mast cells. By overexpressing Txk in T cells throughout development, we found that Txk specifically augments the phospholipase C (PLC)-γ1–mediated calcium signal transduction pathway upon T cell antigen receptor (TCR) engagement. Although Txk is structurally different from inducible T cell kinase (Itk), another Tec family member expressed in T cells, expression of the Txk transgene could partially rescue defects in positive selection and signaling in itk−/− mice. Conversely, in the itk+/+ (wild-type) background, overexpression of Txk inhibited positive selection of TCR transgenic thymocytes, presumably due to induction of cell death. These results identify a role for Txk in TCR signal transduction, T cell development, and selection and suggest that the Tec family kinases Itk and Txk perform analogous functions.

https://rupress.org/jem/article-pdf/190/10/1427/1121619/1427.pdf

A role for the Tec family tyrosine kinase Txk in T cell activation and thymocyte selection.

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Essential Role of LAT in T Cell Development

A role for the Tec family tyrosine kinase Txk in T cell activation and thymocyte selection.