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By taking advantage of the direct interaction between heat shock protein 90 (Hsp90) and the transcriptional repressor Bcl-6, a purine-derived inhibitor of Hsp90 selectively kills diffuse large B cell lymphomas that depend on the expression of Bcl-6 for their survival.
In individuals with 5q– syndrome, deletion within chromosome 5q is associated with hematological abnormalities. Jillian Barlow et al. now create an animal model of the disease using chromosomal engineering to remove a corresponding region of the mouse genome. The resulting hematological abnormalities resemble those in the human disease, and the authors provide genetic evidence that p53 activation contributes to the disease process.
In a new report, Benjamin Alman and his colleagues find that the morphogenic pathway activated by Hedgehog signaling is a key mediator of osteoarthritis, a condition that is marked by irreversible degeneration of the joints and with no current treatment. They also found that blockade of Hedgehog signaling prevented osteoarthritis in a mouse model, suggesting this pathway as a possible target to treat this devastating disease.
In a mouse model of Huntington's disease, synaptic activation of NMDA receptors induces the formation of huntingtin-containing inclusions, rendering neurons more resistant to death in vivo and in vitro. In contrast, stimulation of extrasynaptic NMDA receptors increases neuronal vulnerability by preventing inclusion formation.
For myelodysplastic syndromes caused by deletion of chromosome 5q, Daniel Starczynowski et al. provide evidence that decreased expression of two miRNAs in this region—miR-145 and miR-146a—contributes to abnormal megakaryocyte differentiation and platelet production and progression of the disease to either bone marrow failure or leukemia. The authors also provide a mechanistic explanation for these effects by which loss of these two miRNAs leads to derepression of innate immune signaling.
Rheumatoid arthritis usually begins in one joint but spreads to other joints as the disease progresses. Elena Neumann and her colleagues show that rheumatoid arthritis synovial fibroblasts (RASFs) may be key mediators of this process. They show, using a SCID mouse model, that human RASFs can migrate long distances through the bloodstream from diseased cartilage to unaffected cartilage, where they can mount a new attack.
Transcription factors known for handling the body's response to lipids promote clearance of apoptotic cells by macrophages, according to new research (pages 1266–1272). When this process goes awry, autoimmunity can result.