Reduced Functional Capacity of CD8 +

Mice (I-A(b-/-)) that lack CD4(+) T cells remain healthy for at least three months after respiratory exposure to the murine gamma-herpesvirus 68 (gammaHV68), then succumb with symptoms of chronic wasting disease. Postexposure challenge of gammaHV68-infected I-A(b+/+) and I-A(b-/-) mice with a recombinant vaccinia virus (Vacc-p56) expressing an antigenic gammaHV68 peptide caused a massive increase in the numbers of D(b)p56-specific CD8(+) T cells. Previous experiments showed that, despite the large numbers of potential CTL effectors, there was little effect on the long-term survival of the CD4-deficient group and no diminution in the level of persistent virus shedding and latency. Comparison of the expanded CD8(+)D(b)p56(+) sets in the I-A(b+/+) and I-A(b-/-) mice indicated that these two T cell populations were not identical. More CD69(high)CD8(+) D(b)p56(+) T cells were found in the CD4-deficient mice, an effect that might be thought to reflect higher Ag load. By contrast, the mean fluorescence intensity of staining for the CD44 glycoprotein was diminished on CD8(+)D(b)p56(+) T cells from the I-A(b-/-) group, the level of CTL activity was lower on a per cell basis, and the relative prevalence of IFN-gamma(+)TNF-alpha(+) T cells detected after in vitro stimulation with the p56 peptide was decreased. Given that this experimental system provides an accessible model for evaluating postexposure vaccination protocols that might be used in diseases like HIV/AIDS, the further need is to clarify the underlying molecular mechanisms and the relative significance of lack of CD4(+) T help vs higher Ag load for these expanded CD8(+) effector populations

Rapid diagnosis of medulloblastoma molecular subgroups

Purpose: Microarray studies indicate medulloblastoma comprises distinct molecular disease subgroups, which offer potential for improved clinical management. Experimental Design: Minimal mRNA expression signatures diagnostic for the Wnt/Wingless (WNT) and Sonic Hedgehog (SHH) subgroups were developed, validated, and used to assign subgroup affiliation in 173 tumors from four independent cohorts, alongside a systematic investigation of subgroup clinical and molecular characteristics. Results: WNT tumors [12% (21/173)] were diagnosed >5 years of age (peak, 10 years), displayed classic histology, CTNNB1 mutation (19/20), and associated chromosome 6 loss, and have previously been associated with favorable prognosis. SHH cases [24% (42/173)] predominated in infants (<3 years) and showed an age-dependent relationship to desmoplastic/nodular pathology; all infant desmoplastic/nodular cases (previously associated with a good outcome) were SHH-positive, but these relationships broke down in noninfants. PTCH1 mutations were common [34% (11/32)], but PTCH1 exon1c hypermethylation, chromosome 9q and REN (KCTD11) genetic loss were not SHH associated, and SMO or SUFU mutation, PTCH1 exon1a or SUFU hypermethylation did not play a role, indicating novel activating mechanisms in the majority of SHH cases. SHH tumors were associated with an absence of COL1A2 methylation. WNT/SHH-independent medulloblastomas [64% (110/173)] showed all histologies, peaked at 3 and 6 years, and were exclusively associated with chromosome 17p loss. Conclusions: Medulloblastoma subgroups are characterized by distinct genomic, epigenomic and clinicopathologic features, and clinical outcomes. Validated array-independent gene expression assays for the rapid assessment of subgroup affiliation in small biopsies provide a basis for their routine clinical application, in strategies including molecular disease-risk stratification and delivery of targeted therapeutics

Cross-species genomics matches driver mutations and cell compartments to model ependymoma.

Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult since their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown1–3. We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human ependymoma, a form of neural tumor that arises throughout the central nervous system (CNS). Subgroup specific alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. To select cellular compartments most likely to give rise to subgroups of ependymoma, we matched the transcriptomes of human tumors to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus. The transcriptome of human cerebral ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf(−/−) NSCs. Remarkably, activation of Ephb2 signaling in these, but not other NSCs, generated the first mouse model of ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human cerebral tumor. Further comparative analysis of matched mouse and human tumors revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup specific driver mutations with cellular compartments to model and interrogate cancer subgroups