CHOP null (-/-) mice have remarkable absence of hepatocellular apoptosis in response to alcohol feeding but no protection against hyperhomocysteinemia, ER stress, and fatty liver. Thus, CHOP up-regulation occurs downstream of and contributes to one manifestation of ER stress, namely, apoptosis. Microarray studies confirmed by PCR analysis and western blotting indicate that genes affected by CHOP are both proapoptotic and antiapoptotic and CHOP induction by ethanol may tip the balance of cell survival and death toward apoptosis.

Malignant peripheral nerve sheath tumors (MPNSTs), driven in part by hyperactive Ras and epidermal growth factor receptor (EGFR) signaling, are often incurable. Testing of therapeutics for MPNST has been hampered by lack of adequate xenograft models. We previously documented that human MPNST cells are permissive for lytic infection by oncolytic herpes simplex viruses (oHSV). Herein we developed and characterized a xenograft model of human MPNST and evaluated the antitumor effects of oHSV mutants (G207 and hrR3) and the EGFR inhibitor, erlotinib. Additive cytotoxicity of these agents was found in human MPNST cell lines, suggesting that EGFR signaling is not critical for virus replication. Mice bearing human MPNST tumors treated with G207 or hrR3 by intraperitoneal or intratumoral injection showed tumor-selective virus biodistribution, virus replication, and reduced tumor burden. oHSV injection demonstrated more dramatic antitumor activity than erlotinib. Combination therapies showed a trend toward an increased antiproliferative effect. Both oHSV and erlotinib were antiangiogenic as measured by proangiogenic gene expression, effect on endothelial cells and xenograft vessel density. Overall, oHSVs showed highly potent antitumor effects against MPNST xenografts, an effect not diminished by EGFR inhibition. Our data suggest that inclusion of MPNSTs in clinical trials of oHSV is warranted.

In an initial epigenetic characterization of diffuse large B-cell lymphoma (DLBCL), we evaluated the DNA methylation levels of over 500 CpG islands. Twelve CpG islands (AR, CDKN1C, DLC1, DRD2, GATA4, GDNF, GRIN2B, MTHFR, MYOD1, NEU-ROD1, ONECUT2 and TFAP2A) showed significant methylation in over 85% of tumors. Interestingly, the methylation levels of a CpG island proximal to FLJ21062 differed between the activated B-cell-like (ABC-DLBCL) and germinal center B-cell-like (GCB-DLBCL) subtypes. In addition, we compared the methylation and expression status of 67 genes proximal (within 500 bp) to the methylation assays. We frequently observed that hypermethylated CpG islands are proximal to genes that are expressed at low or undetectable levels in tumors. However, many of these same genes were also poorly expressed in DLBCL tumors where their cognate CpG islands were hypomethylated. Nevertheless, the proportional reductions in BNIP3, MGMT, RBP1, GATA4, IGSF4, CRABP1 and FLJ21062 expression with increasing methylation suggest that epigenetic processes strongly influence these genes. Lastly, the moderate expression of several genes proximal to hypermethylated CpG tracts suggests that DNA methylation assays are not always accurate predictors of gene silencing. Overall, further investigation of the highlighted CpG islands as potential clinical biomarkers is warranted.

Purpose To determine the recurring DNA copy number alterations (CNAs) in classical Hodgkin lymphoma (HL) by microarray-based comparative genomic hybridization (aCGH) using laser capture micro-dissected CD30+ Hodgkin/Reed-Sternberg (HRS) cells. Experimental Design Archived tissues from 27 CD30+ HL plus control samples were analyzed by DNA microarrays. The HL molecular karyotypes were compared to the genomic profiles of germinal center B cells and treatment outcome (chemotherapy responsive vs. primary refractory disease). Results Gains and losses observed in >35% of HL samples were localized respectively to 22 and 12 chromosomal regions. Frequent gains (>65%) were associated with growth and proliferation, NF-κB activation, cell cycle control, apoptosis, and immune and lymphoid development. Frequent losses (>40%) observed encompassed tumor suppressor genes (SPRY1, NELL1, ID4), transcriptional repressors (TXNIP), SKP2 (ubiquitin ligase component) and an antagonist of NF-κB activation (PPARGC1A). In comparison to the germinal center profiles, the most frequent imbalances in HL were losses in 5p13 (AMACR, GDNF, SKP2), and gains in 7q36 (SHH) and 9q34 (ABL1, CDK9, LCN2, PTGES). Gains (>35%) in the HL chemoresponsive patients housed genes known to regulate T-cell trafficking or NF-κB activation (CCL22, CX3CL1, CCL17, DOK4 and IL10), whereas the refractory samples showed frequent loss of 4q27 (IL2/IL21), 17p12 and 19q13.3 gain (BCL3/RELB). Conclusion We identified non-random CNAs in the molecular karyotypes of classical HL. Several recurring genetic lesions correlated with disease outcome. These findings may be useful prognostic markers in the counseling and management of patients and for the development of novel therapeutic approaches in primary refractory HL.