ABSTRACT
Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and 'eat-me' signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A-knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation-a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited.
Subject(s)
Cell Transformation, Neoplastic/genetics , Loss of Function Mutation , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/therapy , Membrane Proteins/genetics , Molecular Targeted Therapy , Adolescent , Adult , Aged , Aged, 80 and over , Animals , British Columbia/epidemiology , Cells, Cultured , Cohort Studies , Female , Genetic Predisposition to Disease , HEK293 Cells , Humans , Jurkat Cells , Loss of Function Mutation/genetics , Lymphoma, Large B-Cell, Diffuse/epidemiology , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Middle Aged , Molecular Targeted Therapy/methods , Molecular Targeted Therapy/trends , Young AdultABSTRACT
The authors describe the first parasitological survey of protozoal infections on tissue slide sections of field cases processed at the histopathology laboratory of the College of Veterinary Medicine (CVM) at the University of the Philippines Los Baños (UPLB). Over 80% of the field cases were from Region 4 (CALABARZON) and the rest were equally distributed from other areas of the Philippines, namely: Region 2 (Cagayan Valley), Metropolitan Manila (National Capital Region), Region III (Central Luzon) and Region VI (Western Visayas). Histopathological analyses of tissue sections from 51 archived cases (1972-2010) of parasitic aetiology were performed. Microscopic examination of a total of 286 histopathological slides revealed the presence of several protozoa, including sarcosporidiosis, hepatic coccidiosis, intestinal coccidiosis, balantidiosis and leucocyto-zoonosis. In addition, the finding of Balantidium and Sarcocystis may have zoonotic implications and can therefore be used as markers of public health importance.
Subject(s)
Protozoan Infections, Animal/pathology , Animals , Philippines , Retrospective Studies , Schools, VeterinaryABSTRACT
The partial nucleotide sequence of putative Trypanosoma brucei rhodesiense oligosaccharyl transferase gene was previously reported. Here, we describe the determination of its full-length nucleotide sequence by Inverse PCR (IPCR), subsequent biological sequence analysis and transmembrane topology modelling. The full-length DNA sequence has an Open Reading Frame (ORF) of 2406 bp and encodes a polypeptide of 801 amino acid residues. Protein and DNA sequence analyses revealed that homologues within the genome of other kinetoplastid and various origins exist. Protein topology analysis predicted that Trypanosoma brucei rhodesiense putative oligosaccharyl transferase clone II (TbOST II) is a transmembrane protein with transmembrane helices in probably an N(cytosol)-C(cytosol) orientation. Data from the GenBank database assembly and sequence analyses in general clearly state that TbOST II is the STT3 subunit of OST in T.b. rhodesiense that necessitates further characterisation and functional studies with RNAi. TbOST II sequence had been deposited in the GenBank (accession number GU245937).
