Blastic plasmacytoid dendritic cell neoplasm: genomics mark epigenetic dysregulation as a primary therapeutic target.
Blastic plasmacytoid dendritic cell neoplasm: genomics mark epigenetic dysregulation as a primary therapeutic target.
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DOI：
10.3324/haematol.2018.202093
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发表时间：
2019-04
期刊：
影响因子：
10.1
通讯作者：
Pileri SA
中科院分区：
文献类型：
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作者：
Sapienza MR;Abate F;Melle F;Orecchioni S;Fuligni F;Etebari M;Tabanelli V;Laginestra MA;Pileri A;Motta G;Rossi M;Agostinelli C;Sabattini E;Pimpinelli N;Truni M;Falini B;Cerroni L;Talarico G;Piccioni R;Amente S;Indio V;Tarantino G;Brundu F;Paulli M;Berti E;Facchetti F;Dellino GI;Bertolini F;Tripodo C;Rabadan R;Pileri SA
母细胞性浆细胞样树突状细胞肿瘤（BPDCN）是一种罕见的侵袭性血液系统恶性肿瘤，目前尚无有效的治疗方法。为了鉴定对新治疗设计有用的遗传改变，我们使用全外显子组测序来分析14名BPDCN患者和患者来源的CAL-1细胞系。突变数据的功能富集分析报告表观遗传调控程序被最显著地破坏（P<0.0001）。特别是，发现25种表观遗传修饰因子发生突变（例如ASXL 1、TET 2、SUZ 12、ARID 1A、PHF 2、CHD 8）; ASXL 1是最常受影响的（28.6%的病例）。为了评估鉴定的表观遗传突变在基因表达和组蛋白H3赖氨酸27三甲基化/乙酰化水平上的影响，我们进行了额外的RNA和病理组织染色质免疫沉淀测序实验。这些患者表现出丰富的基因特征，由甲基化调节，可通过地西他滨给药进行修饰，共享共同的H3 K27乙酰化区域，并具有一组异常上调的细胞周期基因，并由启动子乙酰化标记。总的来说，测序数据的整合显示了基于表观遗传剂的治疗的潜力。通过采用通过CAL-1细胞系异种移植建立的临床前BPDCN小鼠模型，我们证明了表观遗传药物5 '-氮杂胞苷和地西他滨的组合在体内控制疾病进展中的功效。
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effective therapy. In order to identify genetic alterations useful for a new treatment design, we used whole-exome sequencing to analyze 14 BPDCN patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program to be the most significantly undermined (P<0.0001). In particular, twenty-five epigenetic modifiers were found mutated (e.g. ASXL1, TET2, SUZ12, ARID1A, PHF2, CHD8); ASXL1 was the most frequently affected (28.6% of cases). To evaluate the impact of the identified epigenetic mutations at the gene-expression and Histone H3 lysine 27 trimethylation/acetylation levels, we performed additional RNA and pathology tissue-chromatin immunoprecipitation sequencing experiments. The patients displayed enrichment in gene signatures regulated by methylation and modifiable by decitabine administration, shared common H3K27-acetylated regions, and had a set of cell-cycle genes aberrantly up-regulated and marked by promoter acetylation. Collectively, the integration of sequencing data showed the potential of a therapy based on epigenetic agents. Through the adoption of a preclinical BPDCN mouse model, established by CAL-1 cell line xenografting, we demonstrated the efficacy of the combination of the epigenetic drugs 5’-azacytidine and decitabine in controlling disease progression in vivo.