Analysis of HLA-A24-restricted peptides of carcinoembryonic antigen using a novel structure-based peptide–human leukocyte antigen docking algorithm
Although carcinoembryonic antigen (CEA) is a very commonly used tumor marker, CEA-associated immunological responses have not been fully characterized. Previous studies have identified the human leukocyte antigen (HLA)-A2 CEA epitope. Human leukocyte antigens are cell surface molecules that induce a specific immune response by binding antigen peptides and presenting this HLA–peptide complex to T lymphocytes. Nakamura and colleagues sought to further characterize CEA immunological responses and to identify potent HLA-A24-restricted CTL epitope peptides. Only approximately bound peptides with a high affinity can trigger a potent immune response. Nakamaru and colleagues therefore developed an in silico docking simulation assay system to assess the affinity between the HLA-A24 molecule and A24-restricted peptides. The affinity calculated in the docking simulation significantly correlated with MHC stabilization assay scores, but not with the Bioinformatics and Molecular Analysis Section (BIMAS) scores. The authors suggest that the in silico assay system has potential advantages over BIMAS for epitope prediction.
Loss of RUNX3 expression by histone deacetylation is associated with biliary tract carcinogenesis
The RUNX3 gene is a candidate tumor suppressor gene that encodes a protein from the runt domain family of transcription factors, which act as master regulators of gene expression in major developmental pathways. RUNX3 is localized in 1p36, a region that is frequently inactivated by hypermethylation, histone modulation, and other tumor processes. Shio and colleagues previously showed that RUNX3 gene expression is silenced by hypermethylation of the promoter region in 70% of biliary tract cancer cell lines, suggesting that RUNX3 plays a critical role in biliary cancers. In this issue, Shio and colleagues report the results of examination of 17 human biliary cancer specimens. Thirteen specimens had suppressed RUNX3 expression; this decreased expression was related to decreased accumulation of acetylated histone H3 associated with RUNX3. In vitro experiments showed that vorinostat, a highly potent histone deacetylase inhibitor, restored RUNX3 expression in Mz-ChA-2 cells. The results suggest that histone deacetylation-associated suppression of RUNX3 expression plays a significant role in biliary tract carcinogenesis and that vorinostat may hold potential for treatment.
Increased c-Myc activity and DNA damage in hematopoietic progenitors precede myeloproliferative disease in Spa-1 deficiency
Chronic myelogenous leukemia, a disorder of hematopoietic stem cells, begins as chronic myeloproliferative disease (MPD) and progresses to acute leukemia called blast crisis. Deregulated activation of Rap, a Ras-family GTPase, in hematopoietic progenitor cells (HPCs) may cause MPD and leukemia. Tanaka and colleagues previously reported that mice deficient for Spa-1 encoding Rap GTPase-activating protein typically showed deregulated Rap activation in HPCs and developed late-onset MPD with frequent blast crises. To elucidate the mechanisms of MPD development and its late onset, Tanaka and colleagues investigated the features of Spa-1−/− HPCs prior to overt hematologic disorder. Preleukemic, disease-free Spa-1−/− mice showed steady-state hematopoiesis and reduced resistance to whole body γ-ray irradiation, which was attributable to a sustained p53 response in HPCs caused by DNA damage and c-Myc overexpression. The authors suggest that increased c-Myc expression and DNA damage in HPCs precede MPD development in Spa-1−/− mice, leading to a sustained p53 response that acts as a barrier to MPD onset and blast crises progression.