Definitive hematopoiesis requires the mixed-lineage leukemia gene.
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.
Ernst
Patricia
P
Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Departments of Pathology and Medicine, Harvard Medical School, Boston, MA 02115 USA.
Fisher
Jill K
JK
Avery
William
W
Wade
Stacey
S
Foy
Daniel
D
Korsmeyer
Stanley J
SJ
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D001011:Aorta / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004622:Embryo, Mammalian; D005434:Flow Cytometry / Q000379:methods; D005697:Galactosides / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D011495:Histone-Lysine N-Methyltransferase; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007211:Indoles / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D038041:Lymphopoiesis / Q000187:drug effects / Q000502:physiology; D008650:Mesonephros / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011519:Proto-Oncogenes; D000071176:Signaling Lymphocytic Activation Molecule Family; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D018952:Antigens, CD34; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D005697:Galactosides; D007211:Indoles; C498972:Ly9 protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011518:Proto-Oncogene Proteins; C499308:Rag2 protein, mouse; C493726:Runx1 protein, mouse; D000071176:Signaling Lymphocytic Activation Molecule Family; D014157:Transcription Factors; C064655:V(D)J recombination activating protein 2; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D017493:Leukocyte Common Antigens; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside