Dual actions of Meis1 inhibit erythroid progenitor development and sustain general hematopoietic cell proliferation
Dual actions of Meis1 inhibit erythroid progenitor development and sustain general hematopoietic cell proliferation
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DOI：
10.1182/blood-2012-01-403139
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发表时间：
2012-07-12
期刊：
影响因子：
20.3
通讯作者：
Murphy, Kenneth M.
中科院分区：
文献类型：
--
作者：
Cai, Mi;Langer, Ellen M.;Murphy, Kenneth M.
髓样亲嗜性病毒整合位点 1 (Meis1) 与 Pbx1 形成异二聚体，增强 Hox 依赖性基因表达，并与白血病发生和 HSC 自我更新相关。在这里，我们确定了 Meis1 在造血发育中的两种独立作用：一种调节细胞增殖，另一种参与巨核细胞谱系发育。首先，我们发现内源性Mesp1间接诱导胚胎干细胞来源的内皮细胞中的Meis1和Meis2。 Meis1和Meis2的过度表达通过维持造血祖细胞处于增殖状态，极大地增强了胚胎干细胞的造血集落的形成（红系集落除外）。其次，Meis1的过度表达抑制了早期红系祖细胞的发育，在体内的巨核细胞-红系祖细胞阶段发挥作用，使发育从红系生成转向巨核细胞发育。 Meis1 的这种先前未被认识的作用可能解释了在 Meis1(-/-) 小鼠中观察到的胚胎致死性，这种致死性是由于淋巴静脉分离失败引起的，并且可能是血小板生成缺陷的结果。这些结果表明Meis1发挥2个独立的功能，其在造血祖细胞增殖中的作用在发育早期发挥作用，因为它影响巨核细胞-红系祖细胞在巨核细胞和红系发育之间的命运选择。 （血。2012；120(2)；335-346）
Myeloid ecotropic viral integration site 1 (Meis1) forms a heterodimer with Pbx1 that augments Hox-dependent gene expression and is associated with leukemo-genesis and HSC self-renewal. Here we identified 2 independent actions of Meis1 in hematopoietic development: one regulating cellular proliferation and the other involved in megakaryocyte lineage development. First, we found that endogenous Mesp1 indirectly induces Meis1 and Meis2 in endothelial cells derived from embryonic stem cells. Overexpression of Meis1 and Meis2 greatly enhanced the formation of hematopoietic colonies from embryonic stem cells, with the exception of erythroid colonies, by maintaining hematopoietic progenitor cells in a state of proliferation. Second, overexpression of Meis1 repressed the development of early erythroid progenitors, acting in vivo at the megakaryocyte-erythroid progenitor stage to skew development away from erythroid generation and toward megakaryocyte development. This previously unrecognized action of Meis1 may ex-plain the embryonic lethality observed in Meis1(-/-) mice that arises from failure of lymphatic-venous separation and can result as a consequence of defective platelet generation. These results show that Meis1 exerts 2 independent functions, with its role in proliferation of hematopoietic progenitors acting earlier in development from its influence on the fate choice at the megakaryocyte-erythroid progenitor between megakaryocytic and erythroid development. (Blood. 2012;120(2);335-346)