SCL/TAL1 expression level regulates human hematopoietic stem cell self-renewal and engraftment
ABSTRACT 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.
- SourceAvailable from: Carmen G Palii
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- "The basic helix-loop-helix (bHLH) protein TAL1 (also called SCL) displays distinct, sometimes opposite, functions in different cell types (Begley and Green, 1999; Lecuyer and Hoang, 2004). Indeed, TAL1 expression is necessary for the specification, survival and competence of haematopoietic stem cells and for the differentiation of megakaryocytes and erythrocytes (Lecuyer and Hoang, 2004; Reynaud et al, 2005; Brunet de la Grange et al, 2006; Souroullas et al, 2009; Lacombe et al, 2010). Yet TAL1, which is normally turned off early in the lymphoid lineage, exhibits oncogenic properties when aberrantly expressed in lymphoid tissue (Condorelli et al, 1996; Kelliher et al, 1996). "
ABSTRACT: TAL1/SCL is a master regulator of haematopoiesis whose expression promotes opposite outcomes depending on the cell type: differentiation in the erythroid lineage or oncogenesis in the T-cell lineage. Here, we used a combination of ChIP sequencing and gene expression profiling to compare the function of TAL1 in normal erythroid and leukaemic T cells. Analysis of the genome-wide binding properties of TAL1 in these two haematopoietic lineages revealed new insight into the mechanism by which transcription factors select their binding sites in alternate lineages. Our study shows limited overlap in the TAL1-binding profile between the two cell types with an unexpected preference for ETS and RUNX motifs adjacent to E-boxes in the T-cell lineage. Furthermore, we show that TAL1 interacts with RUNX1 and ETS1, and that these transcription factors are critically required for TAL1 binding to genes that modulate T-cell differentiation. Thus, our findings highlight a critical role of the cellular environment in modulating transcription factor binding, and provide insight into the mechanism by which TAL1 inhibits differentiation leading to oncogenesis in the T-cell lineage.The EMBO Journal 02/2011; 30(3):494-509. DOI:10.1038/emboj.2010.342 · 10.43 Impact Factor
- "In fact, CML blast crisis may be characterized by a bulk of self-renewing phenotypic GMPs morphologically apparent as myeloid blasts (Jamieson et al., 2004). Lately, lentiviral methods have been established to be able to more efficiently target HSCs (Reynaud et al., 2005) and other cell types that slowly progress through the cell cycle. Finally, retroviral transduction can be used to mark cells in vivo (Shi et al., 2002) and to identify potential leukaemogenic events in the retrovirally induced leukaemias by the use of retroviral insertions and mutagenesis (Li et al., 1999b). "
Chapter: Models for Human LeukaemiasThe Cancer Handbook, 10/2007; , ISBN: 9780470025079