SCL/TAL1 expression level regulates human hematopoietic stem cell self-renewal and engraftment.
The fate of hematopoietic stem cells (HSCs) is regulated through a combinatorial action of proteins that determine their self-renewal and/or their commitment to differentiation. Stem cell leukemia/T-cell acute lymphoblastic leukemia 1 (SCL/TAL1), a basic helix-loop-helix (bHLH) transcription factor, plays key roles in controlling the development of primitive and definitive hematopoiesis during mouse development but its function in adult HSCs is still a matter of debate. We report here that the lentiviral-mediated enforced expression of TAL1 in human CD34+ cells marginally affects in vitro the differentiation of committed progenitors, whereas in vivo the repopulation capacity of the long-term SCID (severe combined immunodeficient) mouse-repopulating cells (LT-SRCs) is enhanced. As a consequence, the production of SRC-derived multipotent progenitors as well as erythroid- and myeloid-differentiated cells is increased. Looking at the lymphoid compartment, constitutive TAL1-enforced expression impairs B- but not T-cell differentiation. Expression of a mutant TAL1 protein that cannot bind DNA specifically impairs human LT-SRC amplification, indicating a DNA-binding dependent effect of TAL1 on primitive cell populations. These results indicate that TAL1 expression level regulates immature human hematopoietic cell self-renewal and that this regulation requires TAL1 DNA-binding activity.
Reynaud
Damien
D
Department of Hematology, Institut Cochin, U567 Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS) UMR 8104, Paris, France.
Ravet
Emmanuel
E
Titeux
Monique
M
Mazurier
Frédéric
F
Rénia
Laurent
L
Dubart-Kupperschmitt
Anne
A
Roméo
Paul-Henri
PH
Pflumio
Françoise
F
D000818:Animals; D018941:Antigens, CD19 / Q000096:biosynthesis; D018952:Antigens, CD34 / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000166:cytology; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016086:Lentivirus / Q000378:metabolism; D016256:Lewis X Antigen / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D051379:Mice; D016513:Mice, SCID; D008957:Models, Genetic; D009154:Mutation; D015514:Oncogene Proteins, Fusion; D011485:Protein Binding; D013601:T-Lymphocytes / Q000166:cytology
D018941:Antigens, CD19; D018952:Antigens, CD34; D047908:Intracellular Signaling Peptides and Proteins; D016256:Lewis X Antigen; D018950:Lipopolysaccharide Receptors; D015514:Oncogene Proteins, Fusion; C071236:STIL protein, human; D049452:Green Fluorescent Proteins; D004247:DNA