SCL/TAL1 expression level regulates human hematopoietic stem cell self-renewal and engraftment

• Published in: Blood 2005-10, Vol.106 (7), p.2318-2328
• Main Authors: Reynaud, Damien, Ravet, Emmanuel, Titeux, Monique, Mazurier, Frédéric, Rénia, Laurent, Dubart-Kupperschmitt, Anne, Roméo, Paul-Henri, Pflumio, Françoise
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD19 - biosynthesis; Antigens, CD34 - biosynthesis; B-Lymphocytes - cytology; Biological and medical sciences; Blotting, Western; Bone Marrow Cells - cytology; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cells, Cultured; DNA - metabolism; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genetic Vectors; Green Fluorescent Proteins - metabolism; Hematopoiesis; Hematopoietic Stem Cells - cytology; Humans; Intracellular Signaling Peptides and Proteins; Lentivirus - metabolism; Lewis X Antigen - biosynthesis; Lipopolysaccharide Receptors - biosynthesis; Mice; Mice, SCID; Models, Genetic; Molecular and cellular biology; Mutation; Oncogene Proteins, Fusion; Protein Binding; T-Lymphocytes - cytology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-02-0557

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.