文章：

CBFβ-MYH11通过调控包含GATA2和KLF1在内的基因程序干扰巨核细胞分化

CBFβ-MYH11 interferes with megakaryocyte differentiation via modulating a gene program that includes GATA2 and KLF1

原文发布日期：2019-03-08

DOI: 10.1038/s41408-019-0194-8

类型: Article

开放获取: 是

英文摘要：

The inv(16) acute myeloid leukemia-associated CBFβ-MYH11 fusion is proposed to block normal myeloid differentiation, but whether this subtype of leukemia cells is poised for a unique cell lineage remains unclear. Here, we surveyed the functional consequences of CBFβ-MYH11 in primary inv(16) patient blasts, upon expression during hematopoietic differentiation in vitro and upon knockdown in cell lines by multi-omics profiling. Our results reveal that primary inv(16) AML cells share common transcriptomic signatures and epigenetic determiners with megakaryocytes and erythrocytes. Using in vitro differentiation systems, we reveal that CBFβ-MYH11 knockdown interferes with normal megakaryocyte maturation. Two pivotal regulators, GATA2 and KLF1, are identified to complementally occupy RUNX1-binding sites upon fusion protein knockdown, and overexpression of GATA2 partly induces a gene program involved in megakaryocyte-directed differentiation. Together, our findings suggest that in inv(16) leukemia, the CBFβ-MYH11 fusion inhibits primed megakaryopoiesis by attenuating expression of GATA2/KLF1 and interfering with a balanced transcriptional program involving these two factors.

摘要翻译： 

inv(16)急性髓系白血病相关的CBFβ-MYH11融合蛋白被认为会阻断正常髓系分化，但该白血病亚型细胞是否注定走向特定细胞谱系仍不明确。本研究通过多组学分析技术，检测了原代inv(16)患者原始细胞中CBFβ-MYH11的功能影响、体外造血分化过程中的表达情况以及细胞系中的敲低效应。结果显示，原代inv(16)急性髓系白血病细胞与巨核细胞和红细胞具有共同的转录组特征和表观遗传决定因子。通过体外分化系统，我们发现CBFβ-MYH11敲低会干扰正常巨核细胞成熟。研究确定GATA2和KLF1这两个关键调控因子在融合蛋白敲低后互补性占据RUNX1结合位点，且GATA2的过表达可部分诱导巨核细胞定向分化相关基因程序。综上，我们的研究结果表明在inv(16)白血病中，CBFβ-MYH11融合蛋白通过减弱GATA2/KLF1表达并干扰二者参与的平衡转录程序，从而抑制已启动的巨核细胞分化进程。

原文链接：

CBFβ-MYH11 interferes with megakaryocyte differentiation via modulating a gene program that includes GATA2 and KLF1