RESUMO
Small B-cell lymphoma is the classification of B-cell chronic lymphoproliferative disorders that include chronic lymphocytic leukaemia/small lymphocytic lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. The clinical presentation is somewhat heterogeneous, and its occurrence and development mechanisms are not yet precise and may involve epigenetic changes. Epigenetic alterations mainly include DNA methylation, histone modification, and non-coding RNA, which are essential for genetic detection, early diagnosis, and assessment of treatment resistance in small B-cell lymphoma. As chronic lymphocytic leukemia/small lymphocytic lymphoma has already been reported in the literature, this article focuses on small B-cell lymphomas such as follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom macroglobulinemia. It discusses recent developments in epigenetic research to diagnose and treat this group of lymphomas. This review provides new ideas for the treatment and prognosis assessment of small B-cell lymphoma by exploring the connection between small B-cell lymphoma and epigenetics.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma de Zona Marginal Tipo Células B , Linfoma Folicular , Linfoma de Célula do Manto , Macroglobulinemia de Waldenstrom , Adulto , Epigênese Genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Folicular/diagnóstico , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/patologiaRESUMO
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.
Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Linfoma de Célula do Manto/genética , Mutação Puntual , Regiões Promotoras Genéticas/genética , Telomerase/genética , Transcrição Gênica , Idoso , Idoso de 80 Anos ou mais , Divisão Celular , DNA Mitocondrial/análise , DNA de Neoplasias/genética , Progressão da Doença , Feminino , Dosagem de Genes , Genótipo , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia/genética , Linfoma/genética , Masculino , Pessoa de Meia-Idade , Telômero/ultraestrutura , Carga Tumoral , Macroglobulinemia de Waldenstrom/genéticaRESUMO
The diagnosis of bone marrow (BM) infiltration by Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) poses a diagnostic challenge in hematopathology. No definitive morphology or immunophenotype is able to distinguish between infiltration of paraffin-embedded BM sections by WM/LPL and other indolent lymphomas, in particular those of the splenic marginal zone (SMZL) which may also show plasmacytic maturation. An oncogenic gain-of-function mutation (L265P) in the human MYD88 gene has been found to be present in most cases of WM/LPL, yet is absent in most other cases of B-cell chronic lymphoproliferative disorders (LPD), including SMZL. Here, we compare two newly developed diagnostic protocols for detection of this mutation in paraffin-embedded archival tissues which are particularly applicable to decalcified BM biopsies. Sanger sequencing can easily detect levels of BM infiltration above 15% by WM lymphoplasmacytic cells, while the allele-specific PCR can detect the L265P mutation in BM infiltrations below 1% of lymphoma cells. We show that these methods are easily applicable to archival BM specimens and markedly improve diagnostic accuracy of BM infiltrations by indolent B-cell lymphomas.