Study reveals double-edged role of HDAC1 in T-cell lymphoma

A research team at the Medical University of Vienna has uncovered a complex role for histone deacetylases (HDACs) in the development of anaplastic large cell lymphoma (ALCL), a rare and aggressive form of T-cell lymphoma. The study [1], published in Leukemia, reveals that pharmacological inhibition of HDAC activity can delay or even prevent lymphoma onset in mouse models, while the complete genetic loss of a specific HDAC enzyme can have the opposite effect.

HDACs are enzymes that regulate gene expression by modifying chromatin structure, and they are frequently targeted in cancer drug development. The researchers, led by Gerda Egger and first author Maša Zrimšek, investigated the impact of the HDAC inhibitor entinostat, which is currently in clinical trials. When administered to mice predisposed to ALCL, entinostat was found to significantly delay tumour formation. In patient-derived lymphoma cells resistant to standard therapies, entinostat also demonstrated therapeutic activity, offering a potential new line of treatment.

However, the study also uncovered an unexpected twist: the genetic deletion of HDAC1 in T cells led to faster tumour progression in mice. This suggests that, while pharmacological inhibition of HDACs may slow disease, the complete loss of HDAC1 disrupts chromatin organisation and enhances oncogenic signalling pathways such as PDGFRB-STAT5, ultimately accelerating lymphoma development. These findings point to a protective, tumour-suppressive role for HDAC1 under certain conditions.

The study highlights the complexity of targeting epigenetic enzymes in cancer and underscores the importance of context when developing HDAC-targeted therapies. While ALK-positive ALCL typically responds well to targeted treatment, resistance remains a clinical challenge. The new findings suggest that HDAC inhibitors could provide an effective adjunct therapy for resistant cases.

The work was carried out in collaboration with institutions in Italy, the US, and the UK, including the European Institute of Oncology, Boston Children's Hospital, Harvard Medical School, and the University of Cambridge.

More information online

1. Zrimšek et al., HDAC1 acts as a tumor suppressor in ALK-positive anaplastic large cell lymphoma: implications for HDAC inhibitor therapy, Leukemia