Taginostat, a new quinolone-based HDAC6 inhibitor, promotes apoptosis of chronic lymphocytic leukemia cells in vitro and in vivo by activating STAT4.

Chronic lymphocytic leukemia (CLL) is a hematological malignancy characterized by the accumulation of mature CD5⁺ B cells largely due to defective apoptosis. Prolonged leukemic cell survival has been linked to downregulation of the pro-apoptotic adaptor p66Shc and its transcription factor STAT4, both of which are typically reduced in CLL patients. To date, a clear mechanistic explanation for STAT4 deficiency in CLL has not yet been provided. Restoring STAT4 expression or activating its residual function may represent an attractive therapeutic strategy. Histone deacetylase 6 (HDAC6) directly deacetylates and suppresses STAT4 in T lymphocytes, suggesting that a similar mechanism may operate in CLL cells. In this study, we hypothesized that HDAC6-mediated STAT4 inhibition also occurs in CLL cells and contributes to leukemic cell survival. Accordingly, we tested the potent HDAC6 inhibitor Taginostat (HDAC6 IC50 = 7.9 nM) and found that it enhanced p66Shc expression and restored apoptosis in CLL cells. These effects were reproduced by HDAC6 silencing. Flow cytometric and western blot analyses showed that Taginostat boosted residual STAT4 activity by enhancing its phosphorylation. Moreover, transient transfection with STAT4-luciferase or STAT4-green fluorescent protein (GFP) constructs demonstrated that Taginostat promoted both the nuclear translocation and transcriptional activity of STAT4. In addition, in vivo experiments conducted in the Eµ-TCL1 mouse model of CLL demonstrated that Taginostat treatment counteracted disease development, significantly reducing the leukemia burden. Collectively, these findings validate HDAC6 inhibition as a valuable therapeutic strategy for promoting STAT4 activation in CLL cells, restoring the apoptotic cascade, and counteracting disease progression.