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Management of T-cell malignancies: Bench-to-bedside targeting of epigenetic biology. ​

Literature Information ​

DOI10.3322/caac.70001
PMID40232267
JournalCA: a cancer journal for clinicians
Impact Factor232.4
JCR QuartileQ1
Publication Year2025
Times Cited1
KeywordsEZH2 and DNA‐methyltransferase 3 (DNMT3) inhibitors, epigenetics, histone deacetylase (HDAC), large granular lymphocyte (LGL) leukemia (LGLL), non‐Hodgkin lymphoma
Literature TypeJournal Article, Review
ISSN0007-9235
Pages282-307
Issue75(4)
AuthorsAriana Sabzevari, Johnson Ung, Jeffrey W Craig, Kallesh D Jayappa, Ipsita Pal, David J Feith, Thomas P Loughran, Owen A O'Connor

TL;DR ​

Peripheral T-cell lymphomas (PTCL) demonstrate unique sensitivity to various epigenetically targeted drugs, including histone deacetylase inhibitors, EZH2, and DNMT3 inhibitors, prompting exploration of their potential to replace traditional chemotherapy regimens. This study highlights the genetic mutations linked to epigenetic regulation in PTCL, suggesting it may serve as a model for understanding epigenetic vulnerabilities in cancer and improving treatment outcomes.

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EZH2 and DNA‐methyltransferase 3 (DNMT3) inhibitors · epigenetics · histone deacetylase (HDAC) · large granular lymphocyte (LGL) leukemia (LGLL) · non‐Hodgkin lymphoma

Abstract ​

The peripheral T-cell lymphomas (PTCL) are the only disease for which four histone deacetylase (HDAC) inhibitors have been approved globally as single agents. Although it is not clear why the PTCL exhibit such a vulnerability to these drugs, understanding the biological basis for this activity is essential. Many lines of data have established that the PTCL exhibit marked sensitivity to other epigenetically targeted drugs, including EZH2 and DNMT3 (DNA-methyltransferase 3) inhibitors. Even more compelling is the finding that combinations of drugs targeting the epigenetic biology of PTCL are beginning to produce provocative data, leading some to wonder if these agents can replace historical chemotherapy regimens routinely used for patients with the disease. Simultaneously, the field has identified a spectrum of mutations in genes governing epigenetic biology in many subtypes of PTCL, although the T follicular helper lymphomas, including angioimmunoblastic T-cell lymphoma, appear to be particularly enriched for these genetic features. While the direct relationship between the presence of any one of these mutations and responsiveness to a particular epigenetic drug has yet to be established, it is increasingly accepted that the PTCL may be the prototypical epigenetic disease as no other form of cancer has exhibited such a vulnerability to this diversity of epigenetically targeted agents. Herein, we comprehensively review this esoteric and rapidly evolving field to identify themes and lessons from these experiences that may guide efforts to improve outcomes of patients with T-cell neoplasms. Furthermore, we will discuss how these concepts might be applied to the broader field of cancer medicine.

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Primary Questions Addressed ​

  1. What are the specific mechanisms by which HDAC inhibitors exert their effects on peripheral T-cell lymphomas?
  2. How do mutations in epigenetic regulatory genes influence the treatment outcomes of patients with T-cell malignancies?
  3. What are the potential benefits and drawbacks of combining different epigenetically targeted therapies in the treatment of PTCL?
  4. In what ways might the findings from PTCL research inform treatment strategies for other types of cancer?
  5. How does the sensitivity of PTCL to epigenetic therapies compare to other hematological malignancies, and what implications does this have for future research?

Key Findings ​

Research Background and Purpose ​

Peripheral T-cell lymphomas (PTCLs) represent a rare and heterogeneous group of aggressive malignancies that account for a significant proportion of non-Hodgkin lymphomas. The study aims to explore the unique vulnerabilities of PTCLs to epigenetic therapies, particularly focusing on the roles of histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) inhibitors, and other epigenetically targeted agents. Understanding the underlying epigenetic biology may offer new therapeutic strategies to improve patient outcomes.

Main Methods/Materials/Experimental Design ​

The research encompasses a comprehensive review of existing literature, focusing on the epigenetic mechanisms involved in PTCLs. The authors discuss various epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs, and their roles in tumorigenesis.

The methodological approach can be summarized as follows:

Mermaid diagram

Key Results and Findings ​

  1. Vulnerability to Epigenetic Agents: PTCLs exhibit marked sensitivity to HDAC and DNMT inhibitors, which may replace traditional chemotherapy regimens.
  2. Mutational Landscape: Significant mutations in epigenetic regulators, such as TET2 and DNMT3A, are prevalent in PTCLs, contributing to their pathogenesis.
  3. Clinical Efficacy: Several HDAC inhibitors (e.g., romidepsin, belinostat) and DNMT inhibitors (e.g., azacitidine) have shown promising clinical activity in PTCLs, with ongoing trials exploring their efficacy in combination therapies.
  4. Crosstalk of Epigenetic Modifications: Dysregulation of epigenetic marks influences gene expression and can lead to oncogenesis, highlighting the importance of understanding these interactions for therapeutic targeting.

Main Conclusions/Significance/Innovation ​

The study concludes that PTCLs represent a prototypical model for epigenetic dysregulation in cancer. The unique vulnerabilities of these malignancies to epigenetic therapies provide a significant opportunity for novel treatment approaches. The integration of epigenetic agents with traditional therapies may enhance treatment efficacy and reduce reliance on conventional chemotherapy.

Research Limitations and Future Directions ​

  • Limitations: The study acknowledges the limited understanding of the precise mechanisms by which epigenetic alterations contribute to PTCL pathogenesis and the variability in response to therapies among different PTCL subtypes.
  • Future Directions: Future research should focus on:
    • Identifying predictive biomarkers for treatment response.
    • Optimizing dosing schedules and combination strategies for epigenetic agents.
    • Utilizing multi-omic approaches to unravel the complex interactions of epigenetic modifications in PTCL.

Overall, this research highlights the potential of targeting epigenetic pathways in PTCL and suggests that further exploration could lead to improved therapeutic strategies for patients suffering from these challenging malignancies.

References ​

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Literatures Citing This Work ​

  1. Management of T-cell malignancies: Bench-to-bedside targeting of epigenetic biology. - Ariana Sabzevari;Johnson Ung;Jeffrey W Craig;Kallesh D Jayappa;Ipsita Pal;David J Feith;Thomas P Loughran;Owen A O'Connor - CA: a cancer journal for clinicians (2025)

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