title: Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm with poor prognosis. Acquired telomerase reverse transcriptase gene promoter (TERTp) mutations are among the most frequent somatic non-coding mutations in cancers. In this study, the prevalence of TERTp mutations in 24 MCL and 21 other lymphoid neoplasias (oLN) was investigated. Eight MCL samples (33%) carried TERTp mutations, two homozygous and six heterozygous (seven C228T and one C250T), which directly correlated with higher TERT transcription, mitochondrial DNA copy number, and IGHV mutational status in MCL neoplastic cells. TERTp mutations were not found in oLN. TERTp mutations correlated with more lymphoma proliferation and tumor burden, as suggested by the higher number of lymphoma cells circulating in peripheral blood, and tended to associate with longer MCL telomeres, especially in homozygous mutants, although not statistically significant. Telomere-biology genes were overexpressed in MCL cells in comparison to healthy lymphocytes, but were not influenced by mutation status. The findings described for the first time that acquired TERTp mutations are common in MCL but not in other lymphoid neoplasms. It was also demonstrated that TERTp mutations are associated with higher TERT mRNA expression in MCL cells in vivo and higher tumor burden, suggesting these mutations as a driver event in MCL development and progression.
authors: Laboratorio de Genética de Neoplasias Linfoides, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, C1425AUM, Argentina.
authors: Julieta
authors: J
authors: Panero
authors: Divisão De Hematologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP, 14048-900, Brazil.|Centro de Terapia Celular, Fundação de Amparo À Pesquisa do Estado de São Paulo (FAPESP), Ribeirão Preto, SP, 14048-900, Brazil.
authors: Raquel M
authors: RM
authors: Alves-Paiva
authors: Laboratorio de Genética de Neoplasias Linfoides, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, C1425AUM, Argentina.
authors: Alejandro
authors: A
authors: Roisman
authors: Divisão De Hematologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP, 14048-900, Brazil.|Centro de Terapia Celular, Fundação de Amparo À Pesquisa do Estado de São Paulo (FAPESP), Ribeirão Preto, SP, 14048-900, Brazil.
authors: Barbara A
authors: BA
authors: Santana-Lemos
authors: Divisão De Hematologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP, 14048-900, Brazil.|Centro de Terapia Celular, Fundação de Amparo À Pesquisa do Estado de São Paulo (FAPESP), Ribeirão Preto, SP, 14048-900, Brazil.
authors: Roberto P
authors: RP
authors: Falcão
authors: Divisão De Hematologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP, 14048-900, Brazil.
authors: Gustavo
authors: G
authors: Oliveira
authors: Divisão De Hematologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP, 14048-900, Brazil.
authors: Diego
authors: D
authors: Martins
authors: División Patología Molecular, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, C1425AUM, Argentina.
authors: Carmen
authors: C
authors: Stanganelli
authors: Laboratorio de Genética de Neoplasias Linfoides, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, C1425AUM, Argentina.
authors: Irma
authors: I
authors: Slavutsky
authors: Divisão De Hematologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP, 14048-900, Brazil.|Centro de Terapia Celular, Fundação de Amparo À Pesquisa do Estado de São Paulo (FAPESP), Ribeirão Preto, SP, 14048-900, Brazil.
authors: Rodrigo T
authors: RT
authors: Calado
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002455:Cell Division; D004272:DNA, Mitochondrial / Q000032:analysis; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007938:Leukemia / Q000235:genetics; D008223:Lymphoma / Q000235:genetics; D020522:Lymphoma, Mantle-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000648:ultrastructure; D014158:Transcription, Genetic; D047368:Tumor Burden; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C509186:TERT protein, human; D019098:Telomerase