title: HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance.
abstract: Histone deacetylases (HDACs) play a crucial role in chromatin structure and, consequently, gene expression. Their deregulation has been reported in various cancers. We performed a complete and comprehensive study of the expression of 18 HDACs (including Sirtuin; SIRT) by real-time PCR in a cohort of 200 chronic lymphocytic leukemia (CLL) patients with a median follow-up of 77 mo, and compared it with the results obtained from normal B cells. We also compared HDAC expression at diagnosis and after relapse. We observed significant deregulation (mostly upregulation) of HDACs in CLL. In terms of clinical significance, only HDAC6 was significantly correlated with treatment-free survival (TFS), whereas HDAC3 and SIRT2, 3 and 6 were correlated with overall survival (OS). A multivariate Cox regression stepwise analysis indicated that HDAC6, 7 and 10 and SIRT3 were TFS independent predictors. Interestingly, poor prognosis was associated with an overexpression of HDAC7 and 10 but an underexpression of HDAC6 and SIRT3. Therefore, these factors were combined in a TFS score: patients with a score of 0-1-2, 3 and 4 had a median TFS of 107, 57 and 26 mo, respectively (HR = 4.03, p < 0.0001). For OS, SIRT5 and 6 allowed stratification into 3 groups, with a median OS of > 360, 237 and 94 mo (HR = 6.38, p < 0.0001). However, we could not find statistical differences in HDAC expression after relapse. These results, validated by a 5-fold cross-validation, highlight the complex impact of HDAC expression in CLL clinical course.
authors.affiliation: Laboratory of Clinical Cell Therapy, Faculty of Medicine, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Michaël
authors.initials: M
authors.lastname: Van Damme
authors.forename: Emerence
authors.initials: E
authors.lastname: Crompot
authors.forename: Nathalie
authors.initials: N
authors.lastname: Meuleman
authors.forename: Philippe
authors.initials: P
authors.lastname: Mineur
authors.forename: Dominique
authors.initials: D
authors.lastname: Bron
authors.forename: Laurence
authors.initials: L
authors.lastname: Lagneaux
authors.forename: Basile
authors.initials: B
authors.lastname: Stamatopoulos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000201:enzymology* / Q000473:pathology; D016022:Case-Control Studies; D005312:Fetal Blood / Q000201:enzymology; D005500:Follow-Up Studies; D015973:Gene Expression Regulation, Leukemic; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D012016:Reference Values; D015203:Reproducibility of Results; D056566:Sirtuin 3 / Q000235:genetics; D015854:Up-Regulation
chemical_list: D007527:Isoenzymes; C466093:SIRT3 protein, human; D056566:Sirtuin 3; C447828:HDAC10 protein, human; C433811:HDAC6 protein, human; C543273:HDAC7 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases