Ernst Patricia, Fisher Jill K, Avery William, Wade Stacey, Foy Daniel, Korsmeyer Stanley J
Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Departments of Pathology and Medicine, Harvard Medical School, Boston, MA 02115 USA.
Dev Cell. 2004 Mar;6(3):437-43. doi: 10.1016/s1534-5807(04)00061-9.
The Mixed-Lineage Leukemia (MLL) gene encodes a Trithorax-related chromatin-modifying protooncogene that positively regulates Hox genes. In addition to their well-characterized roles in axial patterning, Trithorax and Polycomb family proteins perform less-understood functions in vertebrate hematopoiesis. To define the role of MLL in the development of the hematopoietic system, we examined the potential of cells lacking MLL. Mll-deficient cells could not develop into lymphocytes in adult RAG-2 chimeric animals. Similarly, in vitro differentiation of B cells required MLL. In chimeric embryos, Mll-deficient cells failed to contribute to fetal liver hematopoietic stem cell/progenitor populations. Moreover, we show that aorta-gonad-mesonephros (AGM) cells from Mll-deficient embryos lacked hematopoietic stem cell (HSC) activity despite their ability to generate hematopoietic progeny in vitro. These results demonstrate an intrinsic requirement for MLL in definitive hematopoiesis, where it is essential for the generation of HSCs in the embryo.
混合谱系白血病（MLL）基因编码一种与三胸节相关的染色质修饰原癌基因，该基因正向调控Hox基因。除了在轴向模式形成中具有明确的作用外，三胸节蛋白和多梳家族蛋白在脊椎动物造血过程中的功能尚不清楚。为了确定MLL在造血系统发育中的作用，我们研究了缺乏MLL的细胞的潜能。在成年RAG-2嵌合动物中，缺乏MLL的细胞无法发育成淋巴细胞。同样，B细胞的体外分化需要MLL。在嵌合胚胎中，缺乏MLL的细胞无法参与胎儿肝脏造血干细胞/祖细胞群体的形成。此外，我们发现，来自缺乏MLL的胚胎的主动脉-性腺-中肾（AGM）细胞尽管能够在体外产生造血后代，但缺乏造血干细胞（HSC）活性。这些结果表明，在确定性造血过程中，MLL是内在必需的，它对于胚胎中造血干细胞的产生至关重要。
