title: Characterization of TET and IDH gene expression in chronic lymphocytic leukemia: comparison with normal B cells and prognostic significance.
abstract: Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in western countries, characterized by a heterogeneous clinical course. Although genetic studies have identified chromosomal aberrations or specific mutations, epigenetic changes have been poorly characterized in CLL.
  
  
  
  We assessed ten-eleven translocations (TET) 1, 2, and 3, isocitrate dehydrogenase (IDH) 1, and 2 messenger RNA (mRNA) expression using real-time PCR on purified leukemic B cells from 214 CLL patients (median follow-up = 75 months, range 1-380), normal peripheral blood B cells (n= 20), and umbilical cord blood B cells (n= 21). The microenvironment influence was assessed after 24 h co-culture of CLL cells with bone marrow mesenchymal stromal cells (BMSC). Finally, 5-hydroxymethylcytosine level (%5-hmC) was assessed by ELISA in CLL cells alone or with microenvironment stimuli.
  
  
  
  TET 1 and 3 and IDH2 were decreased in CLL cells compared with healthy B cells (P= 0.0221, 0.0013, <0.0001, respectively), while IDH1 was overexpressed (P= 0.0037). TET2 and IDH1 were significantly correlated with treatment-free survival (TFS); patients with high TET2/IDH1 expression had a higher median TFS (111 months) than patients with low expression (78 months,P= 0.0071/0.0123). Moreover, TET1 expression decreased (P= 0.0371), while TET3 and IDH2 expression increased (P= 0.0273/0.0039) in co-cultures. However, %5-hmC was not correlated with clinical data and was unchanged following microenvironment stimuli.
  
  
  
  Despite a slight deregulation in CLL cells compared with normal B cells, we identified a significant association between TET/IDH gene expression and prognosis, suggesting that epigenetic changes could potentially be associated with disease progression. Moreover, despite an identical %5-hmC, TET gene expression was influenced by contact with BMSC confirming the crucial role of the microenvironment in CLL pathogenesis.
authors.affiliation: Laboratory of Clinical Cell Therapy, ULB Cancer Research Center (U-CRC), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Route de Lennik, 808, 1070 Brussels, Belgium.
authors.forename: Michaël
authors.initials: M
authors.lastname: Van Damme
authors.affiliation: Laboratory of Clinical Cell Therapy, ULB Cancer Research Center (U-CRC), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Route de Lennik, 808, 1070 Brussels, Belgium.
authors.forename: Emerence
authors.initials: E
authors.lastname: Crompot
authors.affiliation: Department of Hematology (U-CRC), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Meuleman
authors.affiliation: Department of Hematology (U-CRC), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Marie
authors.initials: M
authors.lastname: Maerevoet
authors.affiliation: Department of Hemato-Oncology, Grand Hôpital de Charleroi, Gilly, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Mineur
authors.affiliation: Department of Hematology (U-CRC), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bron
authors.affiliation: Laboratory of Clinical Cell Therapy, ULB Cancer Research Center (U-CRC), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Route de Lennik, 808, 1070 Brussels, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lagneaux
authors.affiliation: Laboratory of Clinical Cell Therapy, ULB Cancer Research Center (U-CRC), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Route de Lennik, 808, 1070 Brussels, Belgium.
authors.forename: Basile
authors.initials: B
authors.lastname: Stamatopoulos
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016019:Survival Analysis
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; C578792:TET3 protein, human; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human
keywords: 5-Hydroxymethylcytosine; Chronic lymphocytic leukemia; IDH; Prognosis; TET