文章：

Meis2作为MN1诱导的白血病中的关键因子

Meis2 as a critical player in MN1-induced leukemia

原文发布日期：2017-09-29

DOI: 10.1038/bcj.2017.86

类型: Original Article

开放获取: 是

英文摘要：

Meningioma 1 (MN1) is an independent prognostic marker for normal karyotype acute myeloid leukemia (AML), with high expression linked to all-trans retinoic acid resistance and poor survival. MN1 is also a potent and sufficient oncogene in murine leukemia models, strongly dependent on the MEIS1/AbdB-like HOX protein complex to transform common myeloid progenitors, block myeloid differentiation, and promote leukemic stem cell self-renewal. To identify key genes and pathways underlying leukemic activity, we functionally assessed MN1 cell phenotypic heterogeneity, revealing leukemic and non-leukemic subsets. Using gene expression profiling of these subsets combined with previously published comparisons of full-length MN1 and mutants with varying leukemogenic activity, we identified candidate genes critical to leukemia. Functional analysis identified Hlf and Hoxa9 as critical to MN1 in vitro proliferation, self-renewal and impaired myeloid differentiation. Although critical to transformation, Meis1 knockdown had little impact on these properties in vitro. However, we identified Meis2 as critical to MN1-induced leukemia, with essential roles in proliferation, self-renewal, impairment of differentiation and disease progression in vitro and in vivo. Here, we provide evidence of phenotypic and functional hierarchy in MN1-induced leukemic cells, characterise contributions of Hlf, Hoxa9 and Meis1 to in vitro leukemic properties, and reveal Meis2 as a novel player in MN1-induced leukemogenesis.

摘要翻译： 

脑膜瘤蛋白1（MN1）是正常核型急性髓系白血病（AML）的独立预后标志物，其高表达与全反式维甲酸耐药及不良预后相关。在鼠白血病模型中，MN1同样是一种强效且功能完备的致癌基因，其转化共同髓系祖细胞、阻断髓系分化并促进白血病干细胞自我更新的能力高度依赖MEIS1/AbdB样HOX蛋白复合物。为解析白血病活性的关键基因与通路，我们通过功能评估发现MN1细胞存在表型异质性，包括白血病亚群和非白血病亚群。通过对这些亚群进行基因表达谱分析，并结合已发表的全长MN1与不同致瘤活性突变体的比较研究，我们确定了白血病发生的关键候选基因。功能分析显示Hlf和Hoxa9对MN1的体外增殖、自我更新及髓系分化受损过程至关重要。尽管Meis1在细胞转化中不可或缺，其敲除在体外对这些特性影响甚微。然而，我们发现Meis2在MN1诱导的白血病中发挥关键作用，在体外和体内实验中均对细胞增殖、自我更新、分化阻滞及疾病进展具有重要调控功能。本研究揭示了MN1诱导白血病细胞中存在的表型与功能层级结构，明确了Hlf、Hoxa9和Meis1在体外白血病特性中的作用，并首次证实Meis2是MN1诱导白血病发生的新关键因子。

原文链接：

Meis2 as a critical player in MN1-induced leukemia