文章：

PTPN11突变型JMML造血干细胞与祖细胞的表观遗传学分析揭示异常组蛋白景观

Epigenetic Profiling ofPTPN11Mutant JMML Hematopoietic Stem and Progenitor Cells Reveals an Aberrant Histone Landscape

原文发布日期：29 October 2023

DOI: 10.3390/cancers15215204

类型: Article

开放获取: 是

英文摘要：

Juvenile myelomonocytic leukemia (JMML) is a deadly pediatric leukemia driven byRASpathway mutations, of which >35% are gain-of-function inPTPN11. Although DNA hypermethylation portends severe clinical phenotypes, the landscape of histone modifications and chromatin profiles in JMML patient cells have not been explored. Using global mass cytometry, Epigenetic Time of Flight (EpiTOF), we analyzed hematopoietic stem and progenitor cells (HSPCs) from five JMML patients withPTPN11mutations. These data revealed statistically significant changes in histone methylation, phosphorylation, and acetylation marks that were unique to JMML HSPCs when compared with healthy controls. Consistent with these data, assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis revealed significant alterations in chromatin profiles at loci encoding post-translational modification enzymes, strongly suggesting their mis-regulated expression. Collectively, this study reveals histone modification pathways as an additional epigenetic abnormality in JMML patient HSPCs, thereby uncovering a new family of potential druggable targets for the treatment of JMML.

摘要翻译： 

幼年型粒单核细胞白血病（JMML）是一种由RAS通路突变驱动的致命性儿童白血病，其中超过35%的病例存在PTPN11功能获得性突变。尽管DNA高甲基化预示着严重的临床表型，但JMML患者细胞中的组蛋白修饰与染色质特征尚未得到系统研究。本研究采用全局质谱流式细胞技术——表观遗传飞行时间（EpiTOF），对五例携带PTPN11突变的JMML患者的造血干祖细胞（HSPCs）进行分析。数据显示，与健康对照组相比，JMML HSPCs在组蛋白甲基化、磷酸化和乙酰化修饰标记上存在统计学显著且特异性的改变。与此一致，通过转座酶可及染色质测序（ATAC-seq）分析发现，编码翻译后修饰酶的基因位点染色质可及性发生显著改变，强烈提示这些酶的表达存在异常调控。本研究首次揭示组蛋白修饰通路是JMML患者HSPCs中存在的又一表观遗传异常，从而为JMML治疗发现了新的潜在药物靶点家族。

原文链接：

Epigenetic Profiling ofPTPN11Mutant JMML Hematopoietic Stem and Progenitor Cells Reveals an Aberrant Histone Landscape