Citations

Significance While CD8 + T cells are essential for antitumor immunity, tumors often evade CD8 + T cell surveillance by immunosuppression. Recent study has shown that tumor-induced β-catenin activation in DCs suppresses CD8 + T cell immunity by inhibiting cross-priming, suggesting that activation of β-catenin in DCs might be a key mechanism tumors use to achieve immunosuppression. This report identified mTOR/IL-10 signaling as a previously unidentified mechanism for β-catenin–dependent inhibition of cross-priming. Surprisingly, our study also revealed that β-catenin in DCs was required for CD8 + T cell maintenance post-clonal expansion, suggesting that β-catenin exerts opposite functions during different stages of CD8 + T cell responses. Based on these findings, we have demonstrated selectively manipulating β-catenin signaling as a feasible strategy to improve DC vaccine efficacy.

Abstract Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3′ untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P < 2.3 × 10−5) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. Significance: Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk. Cancer Discov; 5(4); 368–79. ©2015 AACR. See related commentary by Yousef, p. 351 This article is highlighted in the In This Issue feature, p. 333

Plasma membrane calcium pumps differentially affect the pattern of calcium signals.

SummaryDeubiquitinase enzymes (DUBs) of the proteasomal 19S regulatory particle are emerging as important therapeutic targets in several malignancies. Here we demonstrate that inhibition of two proteasome‐associated DUBs (USP14 and UCHL5) with the small molecule DUB inhibitor b‐AP15, results in apoptosis of human Waldenström macroglobulinaemia (WM) cell lines and primary patient‐derived WM tumour cells. Importantly, b‐AP15 produced proteotoxic stress and apoptosis in WM cells that have acquired resistance to the proteasome inhibitor bortezomib. In silico modelling identified protein residues that were critical for the binding of b‐AP15 with USP14 or UCHL5 and proteasome enzyme activity assays confirmed that b‐AP15 does not affect the proteolytic capabilities of the 20S proteasome β‐subunits. In vitro toxicity from b‐AP15 appeared to result from a build‐up of ubiquitinated proteins and activation of the endoplasmic reticulum stress response in WM cells, an effect that also disrupted the mitochondria. Focused transcriptome profiling of b‐AP15‐treated WM cells revealed modulation of several genes regulating cell stress and NF‐κB signalling, the latter whose protein translocation and downstream target activation was reduced by b‐AP15 in vitro. This is the first report to define the effects and underlying mechanisms associated with inhibition of USP14 and UCHL5 DUB activity in WM tumour cells.

Disease overview: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs.Diagnosis: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V.Risk stratification: The 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), aggressive SM (ASM), SM associated with a clonal non‐MC lineage disease (SM‐AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis.Management: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom‐directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease‐related organ dysfunction; interferon‐α (+/−corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator‐release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib‐sensitive KIT mutation or in KITD816‐unmutated patients. Treatment of SM‐AHNMD is governed primarily by the non‐MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases.Investigational Drugs: Recent data confirms midostaurin's significant anti‐MC activity in patients with advanced SM. Am. J. Hematol. 90:251–262, 2015. © 2015 Wiley Periodicals, Inc.