Document Detail

Histone acetylation and DNA demethylation of T cells result in an anaplastic large cell lymphoma-like phenotype.
MedLine Citation:
PMID:  22899583     Owner:  NLM     Status:  MEDLINE    
A characteristic feature of anaplastic large cell lymphoma is the significant repression of the T-cell expression program despite its T-cell origin. The reasons for this down-regulation of T-cell phenotype are still unknown. To elucidate whether epigenetic mechanisms are responsible for the loss of the T-cell phenotype, we treated anaplastic large cell lymphoma and T-cell lymphoma/leukemia cell lines (n=4, each) with epigenetic modifiers to evoke DNA demethylation and histone acetylation. Global gene expression data from treated and untreated cell lines were generated and selected, and differentially expressed genes were evaluated by real-time reverse transcriptase polymerase chain reaction and western blot analysis. Additionally, histone H3 lysine 27 trimethylation was analyzed by chromatin immunoprecipitation. Combined DNA demethylation and histone acetylation of anaplastic large cell lymphoma cells was not able to reconstitute their T-cell phenotype. Instead, the same treatment induced in T cells: (i) an up-regulation of anaplastic large cell lymphoma-characteristic genes (e.g. ID2, LGALS1, c-JUN), and (ii) an almost complete extinction of their T-cell phenotype including CD3, LCK and ZAP70. In addition, suppressive trimethylation of histone H3 lysine 27 of important T-cell transcription factor genes (GATA3, LEF1, TCF1) was present in anaplastic large cell lymphoma cells, which is in line with their absence in primary tumor specimens as demonstrated by immunohistochemistry. Our data suggest that epigenetically activated suppressors (e.g. ID2) contribute to the down-regulation of the T-cell expression program in anaplastic large cell lymphoma, which is maintained by trimethylation of histone H3 lysine 27.
Maria Joosten; Volkhard Seitz; Karin Zimmermann; Anke Sommerfeld; Erika Berg; Dido Lenze; Ulf Leser; Harald Stein; Michael Hummel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-16
Journal Detail:
Title:  Haematologica     Volume:  98     ISSN:  1592-8721     ISO Abbreviation:  Haematologica     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-01     Completed Date:  2013-11-25     Revised Date:  2013-12-05    
Medline Journal Info:
Nlm Unique ID:  0417435     Medline TA:  Haematologica     Country:  Italy    
Other Details:
Languages:  eng     Pagination:  247-54     Citation Subset:  IM    
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MeSH Terms
Azacitidine / analogs & derivatives,  pharmacology
B-Lymphocytes / drug effects,  metabolism,  pathology
Cell Line, Tumor
Cluster Analysis
DNA Methylation*
Epigenesis, Genetic / drug effects
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
Gene Silencing
Histones / genetics,  metabolism*
Hydroxamic Acids / pharmacology
Inhibitor of Differentiation Protein 2 / genetics,  metabolism
Lymphoma, Large-Cell, Anaplastic / diagnosis,  genetics*,  metabolism*
Promoter Regions, Genetic
T-Lymphocytes / drug effects,  metabolism*,  pathology*
Transcription Factors / genetics,  metabolism
Reg. No./Substance:
0/Histones; 0/Hydroxamic Acids; 0/Inhibitor of Differentiation Protein 2; 0/Transcription Factors; 3X2S926L3Z/trichostatin A; 776B62CQ27/decitabine; M801H13NRU/Azacitidine

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