The Mixed Lineage Leukemia (MLL1, KMT2A) gene is critical for development and maintenance of hematopoietic stem cells (HSCs), however, whether this protein is limiting for HSC development is unknown due to lack of physiologic model systems. Here, we develop an MLL1-inducible embryonic stem cell (ESC) system and show that induction of wild-type MLL1 during ESC differentiation selectively increases hematopoietic potential from a transitional c-Kit⁺/Cd41⁺ population in the embryoid body and also at sites of hematopoiesis in embryos. Single-cell sequencing analysis illustrates inherent heterogeneity of the c-Kit⁺/Cd41⁺ population and demonstrates that MLL1 induction shifts its composition toward multilineage hematopoietic identities. Surprisingly, this does not occur through increasing Hox or other canonical MLL1 targets but through an enhanced Rac/Rho/integrin signaling state, which increases responsiveness to Vla4 ligands and enhances hematopoietic commitment. Together, our data implicate a Rac/Rho/integrin signaling axis in the endothelial to hematopoietic transition and demonstrate that MLL1 actives this axis.

的混合系白血病（MLL1，KMT2A）基因是发展和造血干细胞（HSC）的维护关键的，然而，无论该蛋白质限制性HSC发展是缺乏生理模型系统的未知所致。在这里，我们开发了一种MLL1诱导型胚胎干细胞（ESC）系统，并表明在ESC分化过程中诱导野生型MLL1有选择地从胚状体以及部位的过渡性c-Kit ⁺ / Cd41 ⁺种群中增加造血潜能在胚胎中的造血作用。单细胞测序分析说明了c-Kit ⁺ / Cd41 ⁺固有的异质性并证明MLL1诱导使其组成朝着多谱系造血身份转移。出人意料的是，这不是通过增加Hox或其他典型的MLL1靶点而发生的，而是通过增强的Rac / Rho /整联蛋白信号传递状态发生的，这增加了对Vla4配体的响应并增强了造血作用。总之，我们的数据暗示了Rac / Rho /整联蛋白信号传导轴在内皮细胞向造血细胞的过渡中，并证明MLL1激活了该轴。