RESUMO
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.
Assuntos
Transformação Celular Neoplásica/genética , Mutação com Perda de Função , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/terapia , Proteínas de Membrana/genética , Terapia de Alvo Molecular , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Colúmbia Britânica/epidemiologia , Células Cultivadas , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Células Jurkat , Mutação com Perda de Função/genética , Linfoma Difuso de Grandes Células B/epidemiologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Adulto JovemRESUMO
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).