In This Issue

B cell chronic lymphocytic leukemia (CLL) is a disease in which outcome can be at least partially predicted by whether the patient has mutations in the B cell receptor (BCR) or not; the lack of mutations foretells the worse clinical outcome. Eric Meffre and colleagues determined the role of antibody reactivity and the impact of mutations on CLL antibody specificity (pages 1636–1643). The authors cloned and expressed antibodies from mutated CLL (M-CLL) and unmutated CLL (UM-CLL) B cells and found that UM-CLL B cells expressed highly polyreactive antibodies whereas most M-CLL B cells did not. They conclude that both UM-CLLs and M-CLLs actually originate from common B cell precursors and that the mutations play an important role in the differential development of the disease by altering original BCR autoreactivity. These results further our understanding of how normal B cells become CLL cells.

Protein C (PC) has anti-inflammatory and anticoagulant properties. Patients with defective PC activity suffer from thrombotic complications, which can result in deep vein thrombosis, pulmonary embolism, and stroke. There was thus a need to develop a useful animal model for severe PC deficiency, but this has been difficult since mice with total PC deficiency do not survive the neonatal period and cannot be studied as adults. Francis Castellino and colleagues used a novel transgenic strategy to obtain and characterize mice that express only 2–12% of the normal levels of this protein (pages 1552–1561). The mice survived but they spontaneously developed thrombosis and inflammation. The results also showed that maternal PC is required for sustaining pregnancy, as mothers lacking PC experienced trophoblastic cell death. This new mouse line will be useful for understanding the role of PC in development, disease, and pregnancy complications.

Members of the FGF family of proteins play many regulatory roles in several tissues. FGF-21 is a novel member of the FGF family, but its biological role was not previously known. In this issue, Alexei Kharitonenkov and colleagues describe the bioactivity of FGF-21, provide insights into its mechanism of action, and characterize the role that this molecule plays in modulating critical metabolic parameters in rodents (pages 1627–1635). The researchers show that FGF-21 regulates glucose uptake in mouse and human fat cells. When overexpressed, FGF-21 protected mice from diet-induced obesity. Moreover, therapeutic administration of FGF-21 lowered glucose and triglyceride levels to nearly normal without concomitant hypoglycemia or weight gain in multiple animal models of type 2 diabetes. These results define a functional role for FGF-21 in vivo and provide evidence that pharmacological manipulation of FGF-21 may be effective in the treatment of diabetes.

Congenital heart defects are the most common abnormality in newborns. Mutations in single genes involved in normal heart development and morphogenesis have been found to cause some cases of congenital heart defects. One such gene is Gata4, mutations of which are found in humans and have been associated with congenital heart disease due to atrial or ventricular septal defects. In this issue of the JCI, William Pu and colleagues evaluated the function of Gata4 in the myocardium by inactivation of the gene both early and late in heart development (pages 1522–1531). They found that Gata4 regulates the formation of the right ventricle in a stage-specific manner. Gata4 is also essential for normal rates of cardiomyocyte proliferation and for formation of the heart valves. These results suggest that Gata4 is a candidate gene for congenital heart disease associated with defective development of the right ventricle.