Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with Nuclear factor kappa B (NF-κB). The role of BTK in primary CNS lymphoma (PCNSL) is unknown. We performed a Phase 1 clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS Lymphoma. Clinical responses to ibrutinib occurred in 10/13 (77%) PCNSL patients, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of Caspase Recruitment Domain Family Member 11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-Cell Antigen Receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with Phosphatidylinositol 3-kinase (PI3K)/mTOR activation markers. Inhibition of the PI3K-isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.

SummaryNuclear receptor signaling plays an important role in energy metabolism. In this study we demonstrate that the nuclear receptor corepressor RIP140 is a key regulator of metabolism in skeletal muscle. RIP140 is expressed in a fiber type-specific manner, and manipulation of its levels in null, heterozygous, and transgenic mice demonstrate that low levels promote while increased expression suppresses the formation of oxidative fibers. Expression profiling reveals global changes in the expression of genes implicated in both myofiber phenotype and metabolic functions. Genes involved in fatty-acid oxidation, oxidative phosphorylation, and mitochondrial biogenesis are upregulated in the absence of RIP140. Analysis of cultured myofibers demonstrates that the changes in expression are intrinsic to muscle cells and that nuclear receptor-regulated genes are direct targets for repression by RIP140. Therefore RIP140 is an important signaling factor in the regulation of skeletal muscle function and physiology.

EGFL7 is a secreted angiogenic factor that is highly conserved in vertebrates. Most secreted angiogenic signaling molecules, including VEGF and fibroblast growth factor-2, are mainly expressed by nonendothelial cell types such as fibroblasts. In contrast, EGFL7 is unique because it is almost exclusively expressed by and acts on endothelial cells. Egfl7 expression is highest when the endothelium is in an active, proliferating state. This factor acts as a chemoattractant for endothelial cells and binds to components of the extracellular matrix. In vivo, Egfl7 is important for regulating tubulogenesis in zebrafish and for controlling vascular patterning and integrity in mice. Its function in blood vessel development is mediated, at least in part, through modulation of Notch signaling. In this review, we summarize the findings that support a role for Egfl7 in developmental and postnatal angiogenesis and describe the EGFL7-signaling pathways that underlie these processes. In addition, we discuss a potential role for EGFL7 in vascular repair and its possible use as a therapeutic target for treatment of hypoxia-induced injury. Finally, we consider EGFL7 action during tumorigenesis and its potential as an antiangiogenic agent. (Blood. 2012;119(6):1345-1352)

Epidermal growth factor-like domain 7 (Egfl7) is important for regulating tubulogenesis in zebrafish, but its role in mammals remains unresolved. We show here that endothelial overexpression of Egfl7 in transgenic mice leads to partial lethality, hemorrhaging, and altered cardiac morphogenesis. These defects are accompanied by abnormal vascular patterning and remodeling in both the embryonic and postnatal vasculature.

RIP140 is a corepressor for nuclear receptors that regulates energy expenditure in adipose tissue by suppressing the expression of clusters of metabolic genes involved in glucose and lipid metabolism. The gene encoding RIP140/Nrip1 contains only one coding exon but has multiple promoters and 5 non-coding exons that are subject to alternative splicing. In adipocytes we have defined a promoter, referred to as P2, that is preferentially utilized and activated during adipogenesis. Expression studies and chromatin immunoprecipitation experiments indicate that estrogen-related receptor ␣ (ERR␣), the level of which increases during adipogenesis in parallel with RIP140, stimulates transcription from the P2 promoter. Further analysis indicates that ERR␣ is capable of activating RIP140 gene transcription by two mechanisms, directly by binding to an estrogen receptor element/ERR element at ؊650/؊633 and indirectly through Sp1 binding sites in the proximal promoter. Thus, the up-regulation of RIP140 by ERR␣ during adipogenesis may provide an inhibitory feedback mechanism to control the expression of many nuclear receptor target genes.Adipogenesis is regulated by the coordinated expression of transcription factors that control the formation and function of white adipose tissue as a fat storage depot. The identification of many of these transcription factors has relied upon the analysis of preadipocyte cell lines, notably 3T3-L1, that can be induced to undergo differentiation upon exposure to a number of hormone signals, namely glucocorticoid, insulin, and inducers of cAMP. This leads to the activation of a cascade of transcription factors including CCAAT enhancer-binding protein ␤, CCAAT enhancer-binding protein ␦, and SREBP1c that then induce the expression of peroxisome proliferator-activated receptor ␥ and CCAAT enhancer-binding protein ␣ and the formation of adipocytes (1-5). Many other transcription factors, such as Krupple-like factor 5 and E2F1, also facilitate adipogenesis by promoting expression of peroxisome proliferatoractivated receptor ␥, whereas some, such as E2F4 and GATA2/3 that are inhibitory, are down-regulated during adipogenesis (6 -9). The importance of these transcription factors has been confirmed by the analysis of mouse gene knockouts, but CCAAT enhancer-binding protein ␣ and peroxisome proliferator-activated receptor ␥2 appear to play a crucial role, with the latter often regarded as a master regulator of adipogenesis (10 -12).The function of adipose tissue in the control of fat storage and utilization also depends on the transcriptional control of networks of genes. Among the many transcription factors that control metabolic gene networks are nuclear receptors including peroxisome proliferator-activated receptors, thyroid hormone receptors, and estrogen-related receptors (ERRs) 2 (11-17). The ability of nuclear receptors to regulate the expression of genes involved in triglyceride synthesis or fatty acid oxidation is mediated by coactivators and corepressors. Among these are the PGC-1 coactivators ...