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.
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.