HDAC3 inhibition as a therapeutic strategy in T-cell acute lymphoblastic leukemia via the TYK2-STAT1-BCL2 signaling pathway.

INTRODUCTION: Few advances have been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL). Approaches targeting histone deacetylases (HDAC) have not been thoroughly investigated in T-ALL. However, the underlying molecular mechanism of HDAC inhibition remains to be fully elucidated.

OBJECTIVES: The study aimed to evaluate the clinical outcome of chidamide (an oral selective HDAC inhibitor for HDAC1, HDAC2, HDAC3, and HDAC10) in combination with chemotherapy in relapsed or refractory T-ALL and explore the underlying molecular mechanism of HDAC inhibition in T-ALL.

METHODS: The clinical outcomes of 28 patients with relapsed or refractory T-ALL, who received chidamide in combination with chemotherapy were first evaluated. Chidamide (30mg per dose) was orally administered twice a week for a total of four doses (120mg in total per patient) during the first 2 weeks of the combined salvage chemotherapy. Transcriptomic analysis was used to identify pivotal signaling pathways of histone deacetylase inhibition in T-ALL cell lines. Short hairpin RNA-mediated inhibition, co-immunoprecipitation, and a series of functional assays were performed to verify the putative signaling pathways involved in cell lines, primary patient samples, and mouse models.

RESULTS: Of the 28 patients, 16 achieved a complete response and three achieved a partial response. As an inhibitor of histone deacetylases, chidamide significantly suppressed the proliferation of T-ALL cells and induced apoptosis and cell cycle arrest in vitro. Chidamide treatment significantly inhibited the protein level of HDAC3, but not HDAC1, HDAC2, or HDAC10, in T-ALL cell lines and primary human T-ALL cells. Moreover, the TYK2-STAT1-BCL2 signaling pathway was also substantially inhibited upon chidamide administration. Finally, overexpression of HDAC3 and TYK2 rescued the inhibitory effects of chidamide on T-ALL cells. HDAC3 was found to associate with TYK2 and contributed to activation of the TYK2-STAT1-BCL2 signaling pathway in T-ALL cells.

CONCLUSION: Our results highlight the effectiveness of the combination of chidamide and chemotherapy in the treatment of T-ALL patients and suggest that HDAC3 can act as a potential novel therapeutic target to inhibit the TYK2-STAT1-BCL2 signaling pathway in T-ALL.