Taginostat, an HDAC6 inhibitor, activates STAT4, restoring apoptosis and reducing CLL burden.

Chronic lymphocytic leukemia (CLL) is a hematological malignancy marked by the accumulation of mature CD5⁺ B cells, primarily due to defective apoptosis. This prolonged cell survival is linked to reduced levels of the pro-apoptotic adaptor p66Shc and its transcription factor STAT4 in patients. While STAT4 deficiency is a known issue, its precise mechanistic explanation in CLL has been unclear. HDAC6 directly deacetylates and suppresses STAT4 in T lymphocytes, suggesting a potential role in CLL cell survival by inhibiting STAT4.

Researchers hypothesized that HDAC6-mediated STAT4 inhibition contributes to CLL cell survival. They tested Taginostat, a potent HDAC6 inhibitor with an IC50 of 7.9 nM, on CLL cells in vitro and in the Eµ-TCL1 mouse model of CLL. In vitro, they assessed p66Shc expression and apoptosis. They used flow cytometry and western blot to analyze STAT4 phosphorylation, and STAT4-luciferase or STAT4-green fluorescent protein (GFP) constructs to evaluate STAT4's nuclear translocation and transcriptional activity. In vivo, they monitored leukemia burden in treated mice.

Taginostat treatment significantly enhanced p66Shc expression and restored apoptosis in CLL cells, effects also observed with HDAC6 silencing. Flow cytometric and western blot analyses revealed that Taginostat boosted residual STAT4 activity by enhancing its phosphorylation. Transient transfection experiments with STAT4-luciferase or STAT4-GFP constructs further demonstrated that Taginostat promoted both the nuclear translocation and transcriptional activity of STAT4. These findings indicate a direct role for HDAC6 inhibition in activating STAT4's pro-apoptotic functions. > In vivo experiments using the Eµ-TCL1 mouse model of CLL showed that Taginostat treatment counteracted disease development, significantly reducing the leukemia burden.