T-cell lymphomas encompass a heterogeneous group of cancers that originate from T-lymphocytes, essential cells of the immune system responsible for the targeted destruction of infected or malignant cells. Within this spectrum, Anaplastic Large Cell Lymphoma (ALCL) stands out as a particularly aggressive subtype of non-Hodgkin lymphoma, characterized by the presence of large, abnormal lymphocytes expressing the CD30 marker. ALCL exhibits a notable prevalence in children and young adults, underscoring the urgency for effective treatment strategies. Recent research has brought to light the critical and previously unrecognized role of a specific enzyme, Histone Deacetylase 1 (HDAC1), in inhibiting tumor growth in ALCL. This unexpected discovery, published in the journal Leukemia in 2025, deepens our understanding of the intricate molecular mechanisms driving lymphoma development and presents promising new directions for therapeutic intervention.
Anaplastic Large Cell Lymphoma (ALCL) represents a rare subset of non-Hodgkin lymphomas, accounting for approximately 3% of adult cases and a higher proportion, 10-20%, in pediatric populations. The estimated incidence in the United States is around 0.25 cases per 100,000 individuals. ALCL is not a uniform entity but is classified into several subtypes, primarily based on the expression of the Anaplastic Lymphoma Kinase (ALK) protein and the location of the disease. The main categories include ALK-positive systemic ALCL, ALK-negative systemic ALCL, primary cutaneous ALCL (confined to the skin), and breast implant-associated ALCL. ALK-positive systemic ALCL is more frequently diagnosed in younger patients and generally carries a more favorable prognosis, while ALK-negative systemic ALCL is more common in older adults.
Current treatment strategies for systemic ALCL typically involve combination chemotherapy regimens as the initial approach. Commonly used regimens include CHOP and CHOEP, which employ a combination of cytotoxic drugs to target and destroy lymphoma cells. Brentuximab vedotin, an innovative antibody-drug conjugate that specifically targets the CD30 protein on ALCL cells, has also become a critical component of treatment, particularly for patients experiencing relapse or whose lymphoma is refractory to initial chemotherapy. It is also increasingly being incorporated into frontline therapy for certain ALCL cases. For ALK-positive ALCL, targeted therapies that inhibit the activity of the ALK protein, such as crizotinib and alectinib, have demonstrated significant success, especially in the context of relapsed or resistant disease. In select situations, particularly for patients with relapsed or high-risk ALCL, hematopoietic stem cell transplantation may be considered to achieve sustained remission. Notably, histone deacetylase inhibitors (HDACi), including vorinostat, romidepsin, and belinostat, have been approved for treating relapsed or refractory peripheral T-cell lymphomas, which includes some instances of ALCL, indicating that modulating epigenetic mechanisms is a recognized therapeutic avenue in this disease.
Histone Deacetylases (HDACs) are a family of enzymes that play a fundamental role in the regulation of gene expression. They achieve this by removing acetyl groups from lysine residues located on histone proteins, the structural components around which DNA is wrapped. This deacetylation process generally leads to a more condensed chromatin structure, which restricts the access of transcription factors to the DNA, resulting in the repression of gene expression. In humans, a total of 18 HDACs have been identified and classified into four distinct classes (Class I, II, III, and IV) based on their sequence homology, structural features, and dependence on specific cofactors. Classes I, II, and IV rely on zinc ions for their catalytic activity, while Class III HDACs, also known as sirtuins, require the cofactor NAD+.
HDACs are integral to a multitude of cellular processes that extend beyond gene regulation, encompassing cell cycle control, the initiation of cell death pathways, and the process of cell differentiation. Consequently, the dysregulation of HDAC activity has been strongly implicated in the development and progression of various types of cancer, including lymphomas. Aberrant expression or activity of HDACs is a frequent observation in hematological malignancies, such as T-cell lymphomas, including ALCL. In many cancers, HDACs can contribute to the silencing of genes that normally suppress tumor growth and the activation of genes that promote uncontrolled cell proliferation and survival. Histone deacetylase inhibitors (HDACi) represent a class of therapeutic agents specifically designed to block the enzymatic activity of HDACs. By inhibiting HDACs, these drugs lead to an accumulation of acetylated histones, which generally results in a more open chromatin conformation and can reactivate the expression of genes that were previously silenced, including those that function to suppress tumor growth. The clinical success of several HDAC inhibitors in treating various lymphoma subtypes underscores the significant role of epigenetic regulation, mediated by HDACs, in these hematological cancers.
Recent investigations have focused on elucidating the specific roles of individual HDAC isoforms, particularly HDAC1 and HDAC2, in the context of Anaplastic Large Cell Lymphoma (ALCL). In this research, scientists explored the effects of both pharmacological inhibition of HDACs and targeted genetic silencing of specific HDAC isoforms within preclinical models of ALCL. The findings revealed that the use of entinostat, a class I-specific HDAC inhibitor currently being evaluated in clinical trials, led to a notable delay in the development of lymphoma in a mouse model. In some instances, the onset of the disease was even prevented, despite the presence of the NPM::ALK fusion oncogene, a well-known driver of ALK-positive ALCL. Furthermore, entinostat demonstrated efficacy against lymphoma cells derived from patients who had developed resistance to other forms of therapy.
However, in a surprising and seemingly contradictory discovery, when the researchers specifically silenced the gene responsible for producing HDAC1 in T cells within the mouse model, they observed a marked acceleration in the growth of lymphoma. This unexpected result suggests that HDAC1, rather than simply promoting tumor growth as might be generally assumed for an HDAC in cancer, actually plays a protective, tumor-suppressing role in ALCL under certain conditions. Additional experiments involving the genetic loss of HDAC2 in T cells also showed an acceleration of lymphoma development, but the effect was less pronounced than that observed with the loss of HDAC1, indicating a potentially more significant role for HDAC1 in this protective function.
To elucidate the mechanisms underlying HDAC1’s tumor-suppressing activity in ALCL, the researchers conducted detailed molecular analyses. These investigations revealed that the absence of HDAC1 leads to significant alterations in the way the genetic material within T cells is packaged and organized (chromatin structure), which consequently affects the activity of various genes. Specifically, the loss of HDAC1 was found to enhance the activity of key signaling pathways known to be involved in cancer development and progression. These include the PDGFRB-STAT5 (Platelet-Derived Growth Factor Receptor Beta – Signal Transducer and Activator of Transcription 5) signaling pathway and mechanisms associated with the T cell receptor (TCR). These pathways are critical for normal T cell function but can become dysregulated in lymphomas, promoting uncontrolled cell growth, survival, and the ability of cancer cells to spread (dissemination).
It is noteworthy that HDAC1 and its closely related family member HDAC2 have previously been shown to play essential roles in the normal development of T cells and in maintaining the identity of CD4+ T cells by suppressing the expression of genes associated with CD8+ T cells. The loss of these enzymes can disrupt this delicate balance within the T cell lineage. Furthermore, research suggests that HDAC1 and HDAC2 are involved in regulating genes that modulate the activity of the tumor suppressor protein p53, acting as a safeguard to prevent the development of lymphomas driven by the oncogene Myc.
The findings of this research present a complex scenario for the therapeutic application of HDAC inhibitors in ALCL. While broad inhibition of HDAC activity, as observed with entinostat, appears to have anti-tumor effects in preclinical models and even in patient-derived cells, the discovery of HDAC1’s tumor-suppressing role suggests that such broad inhibition might also have unintended consequences by blocking the protective function of HDAC1. Despite this complexity, the study offers hope for the potential use of HDAC inhibitors like entinostat as an additional treatment strategy for ALK-positive ALCL, particularly in patients who have developed resistance to ALK inhibitors or other standard therapies. The contrast between pharmacological inhibition of HDACs and the specific genetic silencing of HDAC1 underscores the need for a more nuanced and precision medicine approach when considering HDAC-targeted therapies for ALCL. Future therapeutic strategies might involve the development of more selective HDAC inhibitors that spare HDAC1 activity or combination therapies that account for the dual roles of HDACs in this disease. The researchers emphasize the importance of future investigations aimed at further elucidating the intricate interactions of HDAC1 with other epigenetic regulators and signaling pathways at different stages of lymphoma development. Identifying specific biomarkers that can predict which patients are most likely to benefit from HDAC inhibitor therapy, while minimizing potential adverse effects related to HDAC1 inhibition, will be a crucial step in translating these findings into clinical practice. The study’s results strongly advocate for the advancement of clinical trials specifically designed to evaluate the efficacy and safety of HDAC inhibitors like entinostat in ALK-positive ALCL patients who have experienced relapse or developed resistance to existing treatments.
The research teams leading this study, including Gerda Egger and first author Maša Zrimšek from the Department of Pathology at the Medical University of Vienna, emphasize the unexpected nature of their findings regarding HDAC1’s protective role in ALCL. They express hope that these results will pave the way for the use of HDAC inhibitors as a valuable addition to the treatment armamentarium for ALK-positive ALCL, particularly in cases where resistance to current therapies has emerged. The researchers also highlight the importance of a personalized approach to cancer treatment, suggesting that investigating the individual molecular characteristics of a patient’s tumor, including the status and activity of HDAC1, could be crucial in guiding treatment decisions and selecting the most appropriate therapeutic strategy. Furthermore, drawing parallels with the successful use of medications that reverse the loss of PD-1 signaling in other cancer types, the scientists suggest exploring similar approaches that could restore HDAC1’s protective function in T cell Non-Hodgkin’s lymphomas, potentially leading to new and effective treatment options. Study leader Gerda Egger stated that although the chances of a cure for ALK-positive ALCL are very good thanks to specific treatments, treatment resistance often occurs, making additional treatment options urgently needed. The present results, according to Dr. Egger, give hope for the use of HDAC inhibitors as an additional treatment option in the near future.
It is important to note that HDAC activity, in general, can be influenced by various lifestyle factors, including diet and exercise. For instance, certain dietary components like butyrate and sulforaphane have been shown to inhibit HDAC activity. Exercise has also been reported to modulate HDAC activity in various tissues. However, the current research primarily focuses on the direct role of HDAC1 within the lymphoma cells themselves in the context of ALCL development. While lifestyle factors might influence overall HDAC activity in the body, the specific impact of these factors on HDAC1’s tumor-suppressing mechanism in ALCL remains an area for future investigation.
In conclusion, the recent identification of Histone Deacetylase 1 (HDAC1) as an important tumor suppressor in ALK-positive Anaplastic Large Cell Lymphoma (ALCL) represents a significant advancement in our understanding of this aggressive T-cell malignancy. This finding is particularly noteworthy given the established role of HDACs in cancer and the current use of HDAC inhibitors in lymphoma treatment. The research demonstrates that while broad pharmacological inhibition of HDACs can delay lymphoma development, the specific loss of HDAC1 in T cells paradoxically accelerates tumor growth. This acceleration is linked to alterations in chromatin structure and the enhanced activity of oncogenic signaling pathways such as PDGFRB-STAT5 and TCR signaling, suggesting that HDAC1 normally acts to restrain these pathways in ALCL. These findings have important implications for the therapeutic application of HDAC inhibitors in ALCL. While drugs like entinostat show promise, especially in overcoming treatment resistance, the protective role of HDAC1 underscores the need for careful consideration and potentially more targeted approaches. Future research endeavors will undoubtedly focus on further unraveling the intricate mechanisms by which HDAC1 exerts its tumor-suppressing activity in ALCL and on identifying biomarkers that can help guide the use of HDAC-targeted therapies in a personalized manner, ultimately aiming to improve treatment outcomes for patients with this challenging lymphoma.
