Volume 23 Issue 2, February 2013

Inflammasomes are multiprotein complexes that detect and respond to foreign and endogenous danger signals by activating caspase-1; active caspase-1, in turn, matures the pro-inflammatory IL-1β family cytokines by cleaving their pro-forms into the biologically active cytokines. The upstream mechanisms leading to inflammasome activation, in particular for the NRLP3 inflammasome, remain poorly understood. Lu and colleagues identify a new function of Protein Kinase R (PKR) for activating the NLRP1, NLRP3, NLRC4 and AIM2 inflammasomes, thus identifying a potential new target for treating inflammasome-mediated diseases.

Seminal studies in C. elegans contributed to our general understanding of programmed cell death conferred by apoptosis. A recent study unravelled a new form of cell death in the worm and provided insights into its regulation. Affected cells are shed from intact tissues, a modality of death likely to be conserved and relevant to cancer.

Interferon-gamma (IFN-γ) is crucial for immunity against different pathogens due to its broad effects on the multiple arms of the immune system. The regulation of IFN-γ immunity is of extensive interest to research as well as practical activity for drug discovery. New evidence supports previous findings that ubiquitin-like protein ISG15 acts as an extracellular cytokine and promotes IFN-γ production, providing intriguing insights of the importance of ISG15 into the control of human mycobacterial disease.

Blood transfusion medicine requires a constant supply of platelets, which is now totally donor dependent. Recent advances in the generation of platelets in vitro through megakaryocytes (MKs) may provide protocols not only via pluripotent stem cells, including induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), but also via induced MKs (iMKs). For the first time, mouse and human fibroblasts are successfully transdifferentiated into iMKs by the introduction of three factors, p45NF-E2, Maf G, and Maf K.

Resistance to molecularly targeted therapies can result from genomic alterations in the tumor cells that reactivate oncogenic signaling. Less is known of tumor cell-extrinsic mechanisms of resistance to targeted therapies. Two recent studies have identified HGF as a soluble factor capable of mediating resistance to BRAF and HER2 inhibitors in a paracrine manner. These new findings suggest an important role for the tumor microenvironment in mediating resistance to molecularly targeted therapies.

The significant correlation between disease aggressiveness and the gene and protein structures of the B-cell receptors (BCRs) expressed on chronic lymphocytic leukemia (CLL) cells, together with the evidence for chronic activation of the BCR pathway, have led to the hypothesis that this leukemia initiates and progresses by selecting normal B lymphocytes reactive with a restricted set of (auto)antigens. A study recently published in Nature identified a novel signal-initiating interaction between the third complementary determining region of the IG heavy chain variable domain (HCDR3) and an epitope in the second framework region (FR2) that appears to be unique to CLL B cells and that calls into question the need for classical antigen binding in the activation and expansion of the leukemic cells. These findings are discussed in the context of available information about the antigen reactivity of CLL B cells and its potential role in clonal survival and drive.