Recent genomic profiling of childhood acute lymphoblastic leukemia (ALL) identified a novel high-risk subtype with a gene expression signature resembling Philadelphia chromosome-positive ALL and a poor prognosis (Ph-like ALL). However, the role of inherited genetic variation in Ph-like ALL pathogenesis remains unknown. In a genome-wide association study (GWAS) of 511 ALL cases and 6,661 non-ALL controls, we identified a single susceptibility locus for Ph-like ALL (GATA3, rs3824662, P=2.17×10−14, odds ratio [OR]=3.85, for Ph-like ALL vs. non-ALL; P=1.05×10−8, OR=3.25, for Ph-like ALL vs. non-Ph-like ALL) that was independently validated. The rs3824662 risk allele was associated with somatic lesions underlying Ph-like ALL (i.e., CRLF2 rearrangement, JAK mutation, and IKZF1 deletion) and directly influenced GATA3 transcription. Finally, GATA3 SNP genotype was also associated with early treatment response and the risk of ALL relapse. Our results provide insights into interactions between host and tumor genomes and their importance in ALL pathogenesis and prognosis.

Background & Aims-We recently identified lysophosphatidic acid (LPA) as a potent antiapoptotic agent for the intestinal epithelium. The objective of the present study was to evaluate the effect of octadecenyl thiophosphate (OTP), a novel rationally designed, metabolically stabilized LPA mimic, on radiation-induced apoptosis of intestinal epithelial cells in vitro and in vivo

Abstract-Carbon monoxide (CO) is generated endogenously by the enzyme heme oxygenase. Although CO is a known vasodilator, cellular signaling mechanisms are poorly understood and are a source of controversy. The goal of the present study was to investigate mechanisms of CO dilation in porcine cerebral arterioles. Data indicate that exogenous or endogenously produced CO is a potent activator of large-conductance Ca 2ϩ -activated K ϩ (K Ca ) channels and Ca 2ϩ spark-induced transient K Ca currents in arteriole smooth muscle cells. In contrast, CO is a relatively poor activator of Ca 2ϩ sparks. To understand the apparent discrepancy between potent effects on transient K Ca currents and weak effects on Ca 2ϩ sparks, regulation of the coupling relationship between these events by CO was investigated. CO increased the percentage of Ca 2ϩ sparks that activated a transient K Ca current (ie, the coupling ratio) from Ϸ62% in the control condition to 100% and elevated the slope of the amplitude correlation between these events Ϸ2.6-fold, indicating that Ca 2ϩ sparks induced larger amplitude transient K Ca currents in the presence of CO. This signaling pathway for CO is physiologically relevant because ryanodine, a ryanodine-sensitive Ca 2ϩ release channel blocker that inhibits Ca 2ϩ sparks, abolished CO dilation of pial arterioles in vivo. Thus, CO dilates cerebral arterioles by priming K Ca channels for activation by Ca 2ϩ sparks. This study presents a novel dilatory signaling pathway for CO in the cerebral circulation and appears to be the first presents of a vasodilator that acts by increasing the effective coupling of Ca 2ϩ sparks to K Ca channels. (Circ Res. 2002;91:610-617.)

The G protein-coupled lysophosphatidic acid 2 (LPA 2 ) receptor elicits prosurvival responses to prevent and rescue cells from apoptosis. However, G protein-coupled signals are not sufficient for the full protective effect of LPA 2 . LPA 2 differs from other LPA receptor subtypes in the C-terminal tail, where it contains a zinc finger-binding motif for the interactions with LIM domain-containing TRIP6 and proapoptotic Siva-1, and a PDZ-binding motif through which it complexes with the NHERF2 scaffold protein. In this report, we identify a unique CXXC motif of LPA 2 responsible for the binding to TRIP6 and Siva-1, and demonstrate that disruption of these macromolecular complexes or knockdown of TRIP6 or NHERF2 expression attenuates LPA 2 -mediated protection from chemotherapeutic agent-induced apoptosis. In contrast, knockdown of Siva-1 expression enhances this effect. Furthermore, a PDZ-mediated direct interaction between TRIP6 and NHERF2 facilitates their interaction with LPA 2 . Together, these results suggest that in addition to G proteinactivated signals, the cooperation embedded in the LPA 2 -TRIP6-NHERF2 ternary complex provides a novel ligand-dependent signal amplification mechanism that is required for LPA 2 -mediated full activation of antiapoptotic signaling.

Lysophosphatidic acid (LPA) and its ether analog alkyl-glycerophosphate (AGP) elicit arterial wall remodeling when applied intralumenally into the uninjured carotid artery. LPA is the ligand of eight GPCRs and the peroxisome proliferator-activated receptor γ (PPARγ). We pursued a gene knockout strategy to identify the LPA receptor subtypes necessary for the neointimal response in a non-injury model of carotid remodeling and also compared the effects of AGP and the PPARγ agonist rosiglitazone (ROSI) on balloon injury-elicited neointima development. In the balloon injury model AGP significantly increased neointima; however, rosiglitazone application attenuated it. AGP and ROSI were also applied intralumenally for 1 hour without injury into the carotid arteries of LPA 1 , LPA 2 , LPA 1&2 double knockout, and Mx1Cre-inducible conditional PPARγ knockout mice targeted to vascular smooth muscle cells, macrophages, and endothelial cells. The neointima was quantified and also stained for CD31, CD68, CD11b, and α-smooth muscle actin markers. In LPA 1 , LPA 2 , LPA 1&2 GPCR knockouts, Mx1Cre transgenic, PPARγ fl/− , and uninduced Mx1CreXPPARγ fl/− mice AGP-and ROSI-elicited neointima was indistinguishable in its progression and cytological features from that of WT C57BL/6 mice. In PPARγ −/− knockout mice, generated by activation of Mx1Cre-mediated recombination, AGP and ROSI failed to elicit neointima and vascular wall remodeling. Our findings point to a difference in the effects of AGP and ROSI between balloon the injury-and the non-injury chemically-induced neointima. The present data provide genetic evidence for the requirement of PPARγ in AGP-and ROSI-elicited neointimal thickening in the non-injury model and reveal that the overwhelming majority of the cells in the neointimal layer express α-smooth muscle actin.