title: Global histone deacetylase enzymatic activity is an independent prognostic marker associated with a shorter overall survival in chronic lymphocytic leukemia patients.
abstract: Histone deacetylases (HDAC) play a crucial role in transcriptional regulation and are often deregulated in many cancers. However, global HDAC enzymatic activity has never been investigated in Chronic Lymphocytic Leukemia (CLL). We measured HDAC activity in protein extracts from CD19+ B-cells purified from 114 CLL patients with a median follow-up of 91 months (range: 11-376). HDAC activity was equivalent in CLL and normal B-cells but higher in patients who died during the study than in living patients (152.1 vs. 65.04 pmol; P = 0.0060). Furthermore, HDAC activity correlated with treatment-free survival (TFS; P = 0.0156) and overall survival (OS; P < 0.0001): patients with low HDAC activity (n = 75) had a median TFS and OS of 101 and > 376 months, respectively, whereas patients with high HDAC activity (n = 39) had a median TFS and OS of 47 and 137 months, respectively. Multivariate analyses indicated that HDAC activity is an independent predictor of OS (hazard ratio = 7.68; P = 0.0017). Finally, HDAC activity increased after B-cell receptor stimulation using IgM, suggesting a role for microenvironment stimuli (n = 10; P = 0.0371). In conclusion, high HDAC activity in CLL B-cells is associated with shorter TFS and OS and is an independent marker of OS, refining the use of other prognostic factors. This work provides a biological base for the use of HDAC inhibitors in CLL treatment.
authors.affiliation: a 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: Barbara
authors.initials: B
authors.lastname: Dessars
authors.forename: Hakim
authors.initials: H
authors.lastname: El Housni
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; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016022:Case-Control Studies; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000401:mortality*; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; D006655:Histone Deacetylases
keywords: B2M, Beta-2-microglobulin; BCR, B cell receptor; CLL, Chronic lymphocytic leukemia; FCR Fludarabine-cyclophosphamide-rituximab; HDAC; HDAC, Histone deacetylase; HDACi, HDAC inhibitor; HR Hazard ratio; IgHV, Immunoglobulin heavy-chain variable-region; LDT, Lymphocyte doubling time; LPL, Lipoprotein lipase; MSC, Mesenchymal stromal cell; NF-κB, Nuclear factor κB; OS, Overall survival; SAHA, Suberoylanilide hydroxamic acid; SIRT, Sirtuin; Sirtuin; TFS, Treatment-free survival; VPA, Valproic acid; ZAP70, Zeta-chain-associated protein kinase 70; chronic lymphocytic leukemia; enzymatic activity; prognosis; sCD23, Soluble CD23