Histone modifier gene mutations in peripheral T-cell lymphoma not otherwise specified.
Histone modifier gene mutations in peripheral T-cell lymphoma not otherwise specified.
复制标题
未另行指定的外周 T 细胞淋巴瘤中的组蛋白修饰基因突变
DOI：
10.3324/haematol.2017.182444
复制
发表时间：
2018-04
期刊：
影响因子：
10.1
通讯作者：
Zhao WL
中科院分区：
文献类型：
--
作者：
Ji MM;Huang YH;Huang JY;Wang ZF;Fu D;Liu H;Liu F;Leboeuf C;Wang L;Ye J;Lu YM;Janin A;Cheng S;Zhao WL
由于外周T细胞淋巴瘤的不同形态和免疫表型特征，大约50%的外周T细胞淋巴瘤是无法分类的，并被归类为外周T细胞淋巴瘤，没有特别说明。这些疾病具有侵袭性的病程和较差的临床结果。迫切需要识别可操作的生物标记物，以开发更好的治疗策略。表观遗传学改变在肿瘤进展中起着至关重要的作用。组蛋白修饰，特别是甲基化和乙酰化，通常涉及染色质状态的调节。在这里，我们筛选了与组蛋白甲基化(KMT2D，SETD2，KMT2A，KDM6A)和乙酰化(EP300，CREBBP)相关的核心基因集，在125例(36.0%)外周T细胞淋巴瘤患者中有45例(36.0%)发现了59个体细胞突变。组蛋白修饰物基因突变与患者较差的无进展生存时间有关，与化疗方案无关，但对组蛋白去乙酰酶抑制剂chidamide的反应增加。在体外，当与去甲基化药物地西他滨联合使用时，奇达胺显著抑制EP300突变的T淋巴瘤细胞和KMT2D突变的T淋巴瘤细胞的生长。机制上，地西他滨与奇达胺协同作用，增强KMT2D与转录因子PU.1的相互作用，调节H3K4me相关信号通路，并使T淋巴瘤细胞对奇达胺增敏。在KMT2D突变的异种移植瘤模型中，Chidamine和Decitabine的双重治疗显著抑制了肿瘤的生长，并通过调节KMT2D/H3K4me轴诱导细胞凋亡。因此，我们的工作有助于理解外周T细胞淋巴瘤中异常的组蛋白修饰，以及可以受益于表观遗传治疗的生物亚群的分层。
Due to heterogeneous morphological and immunophenotypic features, approximately 50% of peripheral T-cell lymphomas are unclassifiable and categorized as peripheral T-cell lymphomas, not otherwise specified. These conditions have an aggressive course and poor clinical outcome. Identification of actionable biomarkers is urgently needed to develop better therapeutic strategies. Epigenetic alterations play a crucial role in tumor progression. Histone modifications, particularly methylation and acetylation, are generally involved in chromatin state regulation. Here we screened the core set of genes related to histone methylation (KMT2D, SETD2, KMT2A, KDM6A) and acetylation (EP300, CREBBP) and identified 59 somatic mutations in 45 of 125 (36.0%) patients with peripheral T-cell lymphomas, not otherwise specified. Histone modifier gene mutations were associated with inferior progression-free survival time of the patients, irrespective of chemotherapy regimens, but an increased response to the histone deacetylase inhibitor chidamide. In vitro, chidamide significantly inhibited the growth of EP300-mutated T-lymphoma cells and KMT2D-mutated T-lymphoma cells when combined with the hypomethylating agent decitabine. Mechanistically, decitabine acted synergistically with chidamide to enhance the interaction of KMT2D with transcription factor PU.1, regulated H3K4me-associated signaling pathways, and sensitized T-lymphoma cells to chidamide. In a xenograft KMT2D-mutated T-lymphoma model, dual treatment with chidamide and decitabine significantly retarded tumor growth and induced cell apoptosis through modulation of the KMT2D/H3K4me axis. Our work thus contributes to the understanding of aberrant histone modification in peripheral T-cell lymphomas, not otherwise specified and the stratification of a biological subset that can benefit from epigenetic treatment.
登录
查看更多内容
影响因子：
20.3
作者：
Kalac, Matko;Scotto, Luigi;O'Connor, Owen A.
通讯作者：
O'Connor, Owen A.
影响因子：
30.8
作者：
da Silva Almeida AC;Abate F;Khiabanian H;Martinez-Escala E;Guitart J;Tensen CP;Vermeer MH;Rabadan R;Ferrando A;Palomero T
通讯作者：
Palomero T
影响因子：
20.3
作者：
Jones, Courtney L.;Gearheart, Christy M.;Carroll, William L.
通讯作者：
Carroll, William L.
影响因子：
30.8
作者：
Huang, Gang;Zhang, Pu;Tenen, Daniel G.
通讯作者：
Tenen, Daniel G.
影响因子：
6.5
作者：
Marchi, Enrica;Zullo, Kelly M.;O'Connor, Owen A.
通讯作者：
O'Connor, Owen A.