Mouse models yield leukemia clues
Twenty patients with X-linked severe combined immunodeficiency (SCID-X1) have been successfully treated with gene therapy – introduction of the therapeutic IL2RG gene by a retroviral vector. But five of the patients developed T-cell leukemias two or more years later because of vector insertion near cancer-causing genes – in four cases, near a known T-cell oncogene, LMO2.
To provide a better mechanistic understanding of SCID-X1 patient leukemias, Utpal Davé, M.D., and colleagues analyzed mouse leukemia models with similar insertional mutations at Lmo2 (mouse LMO2). They report in the May issue of PLoS Genetics that the genes and signaling pathways that are deregulated in the mouse leukemias are also deregulated in sporadic human T-cell leukemias, and are predictive of the leukemias induced in the SCID-X1 patients.
The findings also suggest that IL2RG and LMO2 cooperate in leukemia induction, but require additional mutations. The findings support using mouse models to gain insight into the pathogenesis of T-cell leukemias and may help in designing safer methods for retroviral gene therapy.
— Leigh MacMillan
Branching out in the breast
A process known as “branching morphogenesis” shapes the complex network of ducts that forms during breast development. Although the regulators of this process are poorly understood, proteins called Eph receptors – whose overexpression has been linked to some cancers, including breast cancer – may play a critical role.
Dana Brantley-Sieders, Ph.D., and colleagues have examined the role of the EphA2 receptor in mammary gland branching morphogenesis in mice and cultured cells. In the May 15 Molecular Biology of the Cell, they report that loss of EphA2 inhibits proliferation of mammary epithelium and delays ductal growth into the mammary fat pad. Additionally, EphA2-deficient mammary epithelial cells are unable to branch and do not respond to hepatocyte growth factor, a signal that normally induces branching, in part due to dysfunction of certain molecular “switches” (the Rho GTPase family).
The findings demonstrate an important role for EphA2 receptors in normal mammary gland development, with potential implications for its role in tumor development.
— Melissa Marino
Worms’ molecular stress-relievers
Even worms get stressed, primarily by toxic compounds in their environments. To deal with it, the transcription factor SKN-1 accumulates in the nucleus, where it induces the expression of detoxification enzymes that combat stress and promote longevity. But little is known about the factors that regulate SKN-1 activity, including its accumulation in the nucleus.
Through a genome screen, Keith Choe, Ph.D., and colleagues identified a central regulatory role for a protein called WDR-23, which represses protein levels, nuclear accumulation and activity of SKN-1. With help from another protein complex called CUL4/DDB1, WDR-23 is thought to target SKN-1 for degradation – which prevents nuclear accumulation of SKN-1 under non-stressed conditions.
The findings, published in the May issue of Molecular and Cellular Biology, define a mechanism for how this stress resistance pathway is regulated, which may offer clues about similar detoxification pathways that prevent age-related diseases (like cancer and neurodegeneration) and mediate drug resistance in pathogenic nematodes, microbes and tumor cells.
— Melissa Marino
Staph protein turns on clotting
Acute bacterial endocarditis – infection of the heart’s inner lining or valves – can be deadly, even with antibiotic treatment. Staphylococcus aureus (“staph”) bacteria, a primary cause of endocarditis, latch onto damaged areas of the heart lining or valves and build “vegetations” – protective clot-like clumps of blood platelets, the protein fibrin and bacteria.
Paul Bock, Ph.D., Heather Kroh and Peter Panizzi, Ph.D., are exploring factors secreted by S. aureus that promote blood clotting. They report in the May 12 Proceedings of the National Academy of Sciences that the staph von Willebrand factor-binding protein (VWbp) activates prothrombin – the precursor of the clotting enzyme that converts fibrinogen to fibrin. They define a unique mechanism for VWbp activation of prothrombin that depends on the substrate fibrinogen, and they postulate that this mechanism regulates pathological fibrin deposits during S. aureus endocarditis. Understanding the precise role of VWbp in activating coagulation during endocarditis may aid in the development of mechanism-based treatments for the infection.
— Leigh MacMillan
We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.
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