Lymphomas are a heterogeneous group of complex malignancies that affect the immune system. In lymphoma and other hematological cancers, epigenetics plays a crucial role, as aberrant epigenetic regulation often underlies oncogenesis¹. HDAC1 and HDAC2 are two epigenetic enzymes that control gene expression by modifying chromatin structure, and their deregulated expression or activity is commonly observed in hematological malignancies². By removing acetyl groups from lysine residues on histones, HDACs can alter the transcription of oncogenes and tumor suppressor genes³. In addition, they can deacetylate a large number of non-histone proteins, many of which are also implicated in tumor initiation and progression³. HDACs therefore constitute promising therapeutic targets. Indeed, HDAC inhibitors (HDACi) are already used in the treatment of certain types of lymphoma⁴, and also show potential in re-sensitizing resistant tumor cells⁵. However, while targeting HDACs shows therapeutic potential, maintaining adequate levels of HDAC1/2 is crucial for normal T cell development, as these enzymes are indispensable for preserving the integrity of CD4 lineage T cells⁶, and ensuring genome stability⁷.

In our study, we focused on understanding how HDAC1 and HDAC2 impact the development of ALK-positive anaplastic large cell lymphoma (ALCL), a rare and aggressive lymphoma characterized by the expression of the NPM::ALK fusion oncogene⁸, and explored the potential therapeutic benefits of HDAC inhibition for this particular type of lymphoma.

Key Insights: Tumor-Suppressor Role of HDACs in ALCL

In our publication, HDAC1 acts as a tumor suppressor in ALK-positive anaplastic large cell lymphoma: implications for HDAC inhibitor therapy, we showed that short-term treatment with the HDAC inhibitor Entinostat in an ALCL mouse model delayed or even prevented tumor development, despite persistent NPM::ALK signaling. In contrast, genetic loss of Hdac1 or Hdac2 in T cells accelerated lymphoma development, with HDAC1 loss being more detrimental. Expression of catalytically inactive HDAC1 protein in the Hdac1KO mice showed similar effects to Hdac1 deletion, suggesting that accelerated tumorigenesis mainly depends on the catalytic activity of HDAC1. Correlation of gene expression changes with changes in chromatin accessibility revealed that Hdac1 loss selectively altered cell type specific transcription, essential for T cell signaling and differentiation and hyperactivated oncogenic pathways.

Pharmacological Inhibition vs. Genetic Deletion: Exploring the Complexities

One of the most intriguing findings of this study was the stark difference between pharmacological inhibition and genetic deletion of HDAC1. While we expected similar results, Entinostat treatment prevented tumor formation, while Hdac1 deletion accelerated it. Previous studies have shown that complete loss of HDAC1 and HDAC2 in thymocytes blocks T cell development, while gradual loss of HDAC activity can induce lymphoblastic lymphoma^7,9 - highlighting the complex effects of varying degrees of HDAC inhibition. Moreover, the systemic effects of HDAC inhibition, including its impact on the tumor microenvironment and immune cell compartments, add an additional layer of complexity. We speculate that changes in T cell progenitors in the bone marrow following HDAC inhibitor treatment may contribute to the observed effects, suggesting that the impact of HDAC inhibition extends beyond tumor cells alone.

Why It Matters and Looking Ahead

Our study underscores the critical tumor-suppressive roles of HDAC1 and HDAC2 in ALCL development and, at the same time, demonstrates the therapeutic promise of HDAC inhibitors like Entinostat. Notably, Entinostat exhibited similar efficacy in patient-derived cell lines, whether sensitive or resistant to the ALK inhibitor Crizotinib, emphasizing its potential as a treatment option, even in cases with acquired resistance. Further exploration of the underlying mechanisms is essential, along with the investigation of combination therapies to optimize treatment strategies for ALCL.

References:

1. Hu, D. & Shilatifard, A. Epigenetics of hematopoiesis and hematological malignancies. Genes Dev. 30, 2021–2041 (2016).
2. Wang, P., Wang, Z. & Liu, J. Role of HDACs in normal and malignant hematopoiesis. Mol. Cancer 19, 5 (2020).
3. Li, Y. & Seto, E. HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harb. Perspect. Med. 6, a026831 (2016).
4. Lu, G. et al. Update on histone deacetylase inhibitors in peripheral T-cell lymphoma (PTCL). Clin. Epigenetics 15, 124 (2023).
5. Amengual, J. E. Can we use epigenetics to prime chemoresistant lymphomas? Hematology 2020, 85–94 (2020).
6. Boucheron, N. et al. CD4+ T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2. Nat. Immunol.15, 439–448 (2014).
7. Dovey, O. M. et al. Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice. Blood121, 1335–1344 (2013).
8. Stein, H. et al. CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96, 3681–3695 (2000).
9. Heideman, M. R. et al. Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function. Blood 121, 2038–2050 (2013).