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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression
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The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression

机译：抑癌基因Menin通过影响Hox基因表达来调节造血和髓样转化

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摘要

Menin is the product of the tumor suppressor gene Men1 that is mutated in the inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1). Menin has been shown to interact with SET-1 domain-containing histone 3 lysine 4 (H3K4) methyltrans-ferases including mixed lineage leukemia proteins to regulate homeobox (Hox) gene expression in vitro. Using conditional Men1 knockout mice, we have investigated the requirement for menin in hematopoiesis and myeloid transformation. Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus. Consistent with signaling downstream of menin, ectopic expression of both Hoxa9 and Meis1 rescues colony formation defects in Men1-excised bone marrow. Moreover, Men1 excision also suppresses proliferation of leukemogenic mixed lineage leukemia-AF9 fusion-protein-transformed myeloid cells and Hoxa9 expression. These studies uncover an important role for menin in both normal hematopoiesis and myeloid transformation and provide a mechanistic understanding of menin's function in these processes that may be used for therapy.
机译：Menin是抑癌基因Men1的产物，该基因在遗传性肿瘤综合征多发性内分泌肿瘤1型（MEN1）中发生了突变。 Menin已显示与包含SET-1域的组蛋白3赖氨酸4（H3K4）甲基转移酶相互作用，包括混合谱系白血病蛋白，可在体外调节同源盒（Hox）基因的表达。使用条件Men1基因敲除小鼠，我们调查了造血和髓样转化中对menin的需求。 Men1切除导致Hoxa9表达减少，造血祖细胞集落形成和外周白细胞计数减少。 Menin至少部分地通过与Hoxa9基因座结合，促进H3K4甲基化以及将甲基化的H3K4结合蛋白chd1募集到基因来直接激活Hoxa9表达。与menin下游信号转导一致，Hoxa9和Meis1的异位表达可挽救Men1切除的骨髓中的菌落形成缺陷。此外，Men1切除还抑制了致白血病的混合谱系白血病-AF9融合蛋白转化的髓样细胞的增殖和Hoxa9的表达。这些研究揭示了脑膜素在正常的造血和髓样转化中的重要作用，并提供了对脑膜素在这些可用于治疗的过程中功能的机制的理解。

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