Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling.
Angioimmunoblastic T cell lymphoma (AITL) originates from follicular helper T-cells and is characterised by a polymorphic infiltrate with the neoplastic T-cells forming small clusters around the follicle and high endothelial venules. Despite the recent advances in its phenotypic characterisation, the genetics and molecular mechanisms underlying AITL are not fully understood. In the present study, we performed whole exome sequencing in 9 cases of AITL from Taiwan (n = 6) and U.K. (n = 3). We confirmed frequent mutations in TET2 (9/9), DNMT3A (3/9), IDH2 (3/9), RHOA (3/9) and PLCG1 (2/9) as recently reported by others. More importantly, we identified mutations in TNFRSF21 (1/9), CCND3 (1/9) and SAMSN1 (1/9), which are not yet seen or strongly implicated in the pathogenesis of AITL. Among the pathogenic mutations identified in AITL, mutations in DNA methylation regulators TET2 and DNMT3A occur early in hematopoietic stem cells as shown by previous studies, and these genetic events enhance the self-renewal of hematopoietic stem cells, but are unlikely to have any major impact on T-cell differentiation. Mutations in RHOA, PLCG1 and TNFRSF21 (DR6), which encode proteins critical for T-cell biology, most likely promote T-cell differentiation and malignant transformation, consequently generating the malignant phenotype. Our findings extend the molecular insights into the multistage development of AITL.
Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
Ming
M
Wang
Department of Pathology, Health Science Centre, Peking University, China.|Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
Shaowei
S
Zhang
Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
Shih-Sung
SS
Chuang
Department of Cellular Pathology, Southampton University Hospitals National Health Service Foundation Trust, Southampton, UK.
Margaret
M
Ashton-Key
Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
Eguzkine
E
Ochoa
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.|Department of Oncology and Onco-Hematology, University of Milan, Milan, Italy.|Department of Hematology and Pediatric Onco-Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Niccolo
N
Bolli
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
George
G
Vassiliou
Department of Pathology, Health Science Centre, Peking University, China.
Zifen
Z
Gao
Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
Ming-Qing
MQ
Du
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D056743:Cyclin D3 / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007119:Immunoblastic Lymphadenopathy / Q000235:genetics* / Q000473:pathology; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D051966:Phospholipase C gamma / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000473:pathology*; D020742:rhoA GTP-Binding Protein / Q000235:genetics
D033942:Adaptor Proteins, Vesicular Transport; C534696:CCND3 protein, human; D056743:Cyclin D3; D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; D018124:Receptors, Tumor Necrosis Factor; C435526:SAMSN1 protein, human; C114109:TNFRSF21 protein, human; C066737:RHOA protein, human; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma; D020742:rhoA GTP-Binding Protein
AITL; WES; oncogenic mechanism; somatic mutation