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文献精选 > 近年高分"CRISPR基因编辑"研究（IF≥30，近5年）

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

文献信息 ​

DOI10.3322/caac.70001
PMID40232267
期刊CA: a cancer journal for clinicians
影响因子232.4
JCR 分区Q1
发表年份2025
被引次数1
关键词EZH2和DNA甲基转移酶3（DNMT3）抑制剂、表观遗传学、组蛋白去乙酰化酶（HDAC）、大型颗粒淋巴细胞（LGL）白血病（LGLL）、非霍奇金淋巴瘤
文献类型Journal Article, Review
ISSN0007-9235
页码282-307
期号75(4)
作者Ariana Sabzevari, Johnson Ung, Jeffrey W Craig, Kallesh D Jayappa, Ipsita Pal, David J Feith, Thomas P Loughran, Owen A O'Connor

一句话小结 ​

周边T细胞淋巴瘤（PTCL）对多种表观遗传靶向药物表现出显著敏感性，尤其是HDAC抑制剂和EZH2/DNMT3抑制剂，这表明PTCL可能是一种典型的表观遗传疾病。研究揭示了PTCL亚型中的基因突变谱，尽管尚缺乏直接的药物反应性关系，但这些发现为改善PTCL患者的治疗策略提供了重要线索，并可能对更广泛的癌症治疗产生影响。

在麦伴科研 (maltsci.com) 搜索更多文献 ​

EZH2和DNA甲基转移酶3（DNMT3）抑制剂 · 表观遗传学 · 组蛋白去乙酰化酶（HDAC） · 大型颗粒淋巴细胞（LGL）白血病（LGLL） · 非霍奇金淋巴瘤

摘要 ​

周边T细胞淋巴瘤（PTCL）是唯一一种全球范围内有四种组蛋白去乙酰化酶（HDAC）抑制剂作为单药获批的疾病。尽管尚不清楚为何PTCL对这些药物表现出如此脆弱性，理解这种活性的生物学基础至关重要。大量数据已确立PTCL对其他靶向表观遗传学药物表现出显著敏感性，包括EZH2和DNMT3（DNA甲基转移酶3）抑制剂。更引人注目的是，靶向PTCL表观遗传学的药物组合开始产生引人注目的数据，这使一些人开始思考这些药物是否能替代患者常规使用的历史化疗方案。同时，研究领域已识别出多种PTCL亚型中调控表观遗传学的基因突变谱，尽管T滤泡辅助性淋巴瘤，包括血管免疫母细胞性T细胞淋巴瘤，似乎特别富含这些遗传特征。尽管尚未建立这些突变的存在与对特定表观遗传药物反应性的直接关系，但越来越多的人接受PTCL可能是典型的表观遗传疾病，因为没有其他类型的癌症表现出对这一多样化表观遗传靶向药物的如此脆弱性。在此，我们全面回顾这一深奥而迅速发展的领域，以识别这些经验所传达的主题和教训，指导改善T细胞肿瘤患者的治疗效果。此外，我们还将讨论这些概念如何应用于更广泛的癌症医学领域。

英文摘要 ​

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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主要研究问题 ​

  1. 在PTCL中，HDAC抑制剂的具体作用机制是什么，为什么它们对这种疾病特别有效？
  2. 除了EZH2和DNMT3抑制剂，还有哪些其他的表观遗传学靶向药物可能对PTCL有效？
  3. PTCL的不同亚型在表观遗传学突变方面的差异如何影响治疗策略的选择？
  4. 当前关于表观遗传学药物联合治疗PTCL的临床试验结果有哪些重要发现？
  5. 在PTCL的治疗中，如何评估表观遗传学特征与患者预后之间的关系？

核心洞察 ​

研究背景和目的 ​

外周T细胞淋巴瘤（PTCL）是一类罕见且异质性较强的恶性肿瘤，其对传统化疗的反应较差，预后不佳。近年来，研究发现PTCL对表观遗传学药物（如组蛋白去乙酰化酶（HDAC）抑制剂）的敏感性显著，且已有多种表观遗传靶向药物被批准用于PTCL的治疗。本研究旨在探讨PTCL的表观遗传生物学，评估其对不同表观遗传靶向药物的反应，并为未来的治疗策略提供指导。

主要方法/材料/实验设计 ​

本研究综合了现有的文献和临床数据，重点关注PTCL的表观遗传特征及其对表观遗传靶向药物的反应。以下是研究的技术路线图：

Mermaid diagram

关键结果和发现 ​

  1. 药物敏感性：PTCL对多种表观遗传靶向药物表现出高度敏感，尤其是HDAC抑制剂（如romidepsin和belinostat）和DNMT抑制剂（如5-azacytidine和decitabine）。
  2. 突变谱：在PTCL中，TET2和DNMT3A等基因的突变频繁，且与疾病的临床特征相关。
  3. 组合疗法：初步数据表明，表观遗传靶向药物的组合使用（如HDAC和DNMT抑制剂联合）能够显著提高疗效。

主要结论/意义/创新性 ​

本研究表明，PTCL具有独特的表观遗传学特征，使其成为表观遗传靶向治疗的理想对象。通过靶向表观遗传机制，能够改善PTCL患者的预后，并为开发新的治疗策略提供了理论基础。此外，组合表观遗传药物的应用可能会成为PTCL治疗的未来趋势。

研究局限性和未来方向 ​

  1. 局限性：本研究主要依赖于已有文献，缺乏大规模的临床试验数据来支持结论。
  2. 未来方向：
    • 需要进行更多的临床试验，以验证不同表观遗传药物的组合疗法的有效性。
    • 探索个体化治疗策略，根据患者的表观遗传特征定制治疗方案。
    • 研究表观遗传标志物在PTCL中的作用，以指导临床决策和监测疗效。

参考文献 ​

  1. Angioimmunoblastic T-cell lymphoma contains multiple clonal T-cell populations derived from a common TET2 mutant progenitor cell. - Wen-Qing Yao;Fangtian Wu;Wenyan Zhang;Shih-Sung Chuang;Joe S Thompson;Zi Chen;Shao-Wei Zhang;Alexandra Clipson;Ming Wang;Hongxiang Liu;Hani Bibawi;Yuanxue Huang;Luis Campos;John W Grant;Penny Wright;Hesham Ei-Daly;Lívia Rásó-Barnett;Lorant Farkas;George A Follows;Zifen Gao;Ayoma D Attygalle;Margaret Ashton-Key;Weiping Liu;Ming-Qing Du - The Journal of pathology (2020)
  2. BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1. - Helen Jayne Susan Stewart;Gillian Abigail Horne;Sarah Bastow;Timothy James Telfer Chevassut - Cancer medicine (2013)
  3. Monomorphic epitheliotropic intestinal T-cell lymphoma comprises morphologic and genomic heterogeneity impacting outcome. - Luis Veloza;Doriane Cavalieri;Edoardo Missiaglia;Albane Ledoux-Pilon;Bettina Bisig;Bruno Pereira;Christophe Bonnet;Elsa Poullot;Leticia Quintanilla-Martinez;Romain Dubois;Francisco Llamas-Gutierrez;Céline Bossard;Roland De Wind;Fanny Drieux;Juliette Fontaine;Marie Parrens;Jeremy Sandrini;Virginie Fataccioli;Marie-Hélène Delfau-Larue;Adrien Daniel;Faustine Lhomme;Lauriane Clément-Filliatre;François Lemonnier;Anne Cairoli;Pierre Morel;Sylvie Glaisner;Bertrand Joly;Abderrazak El Yamani;Kamel Laribi;Emmanuel Bachy;Reiner Siebert;David Vallois;Philippe Gaulard;Olivier Tournilhac;Laurence De Leval - Haematologica (2023)
  4. A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma. - Jennifer E Amengual;Renee Lichtenstein;Jennifer Lue;Ahmed Sawas;Changchun Deng;Emily Lichtenstein;Karen Khan;Laine Atkins;Aishling Rada;Hye A Kim;Codruta Chiuzan;Matko Kalac;Enrica Marchi;Lorenzo Falchi;Mark A Francescone;Lawrence Schwartz;Serge Cremers;Owen A O'Connor - Blood (2018)
  5. RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis. - Jose R Cortes;Alberto Ambesi-Impiombato;Lucile Couronné;S Aidan Quinn;Christine S Kim;Ana C da Silva Almeida;Zachary West;Laura Belver;Marta Sanchez Martin;Laurianne Scourzic;Govind Bhagat;Olivier A Bernard;Adolfo A Ferrando;Teresa Palomero - Cancer cell (2018)
  6. Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. - Mark J Kiel;Thirunavukkarasu Velusamy;Delphine Rolland;Anagh A Sahasrabuddhe;Fuzon Chung;Nathanael G Bailey;Alexandra Schrader;Bo Li;Jun Z Li;Ayse B Ozel;Bryan L Betz;Roberto N Miranda;L Jeffrey Medeiros;Lili Zhao;Marco Herling;Megan S Lim;Kojo S J Elenitoba-Johnson - Blood (2014)
  7. Aging, DNA methylation and cancer. - J P Issa - Critical reviews in oncology/hematology (1999)
  8. Writers and readers of histone acetylation: structure, mechanism, and inhibition. - Ronen Marmorstein;Ming-Ming Zhou - Cold Spring Harbor perspectives in biology (2014)
  9. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. - Rita Alaggio;Catalina Amador;Ioannis Anagnostopoulos;Ayoma D Attygalle;Iguaracyra Barreto de Oliveira Araujo;Emilio Berti;Govind Bhagat;Anita Maria Borges;Daniel Boyer;Mariarita Calaminici;Amy Chadburn;John K C Chan;Wah Cheuk;Wee-Joo Chng;John K Choi;Shih-Sung Chuang;Sarah E Coupland;Magdalena Czader;Sandeep S Dave;Daphne de Jong;Ming-Qing Du;Kojo S Elenitoba-Johnson;Judith Ferry;Julia Geyer;Dita Gratzinger;Joan Guitart;Sumeet Gujral;Marian Harris;Christine J Harrison;Sylvia Hartmann;Andreas Hochhaus;Patty M Jansen;Kennosuke Karube;Werner Kempf;Joseph Khoury;Hiroshi Kimura;Wolfram Klapper;Alexandra E Kovach;Shaji Kumar;Alexander J Lazar;Stefano Lazzi;Lorenzo Leoncini;Nelson Leung;Vasiliki Leventaki;Xiao-Qiu Li;Megan S Lim;Wei-Ping Liu;Abner Louissaint;Andrea Marcogliese;L Jeffrey Medeiros;Michael Michal;Roberto N Miranda;Christina Mitteldorf;Santiago Montes-Moreno;William Morice;Valentina Nardi;Kikkeri N Naresh;Yasodha Natkunam;Siok-Bian Ng;Ilske Oschlies;German Ott;Marie Parrens;Melissa Pulitzer;S Vincent Rajkumar;Andrew C Rawstron;Karen Rech;Andreas Rosenwald;Jonathan Said;Clémentine Sarkozy;Shahin Sayed;Caner Saygin;Anna Schuh;William Sewell;Reiner Siebert;Aliyah R Sohani;Reuben Tooze;Alexandra Traverse-Glehen;Francisco Vega;Beatrice Vergier;Ashutosh D Wechalekar;Brent Wood;Luc Xerri;Wenbin Xiao - Leukemia (2022)
  10. Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study. - Lorenzo Falchi;Helen Ma;Sandra Klein;Jennifer K Lue;Francesca Montanari;Enrica Marchi;Changchun Deng;Hye A Kim;Aishling Rada;Alice T Jacob;Cristina Kinahan;Mark M Francescone;Craig R Soderquist;David C Park;Govind Bhagat;Renu Nandakumar;Daniel Menezes;Luigi Scotto;Lubomir Sokol;Andrei R Shustov;Owen A O'Connor - Blood (2021)

引用本文的文献 ​

  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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