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Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene

Abstract

The production of blood cells is sustained throughout the lifetime of an individual by haematopoietic stem cells (HSCs)1. Specification of HSCs from mesoderm during embryonic development requires the stem cell leukaemia SCL/tal-1 gene product2,3,4,5,6. Forced expression of SCL/tal-1 strongly induces blood formation in embryos, indicating that this gene has a dominant role in commitment to haematopoiesis7,8. In the adult haematopoietic system, expression of SCL/tal-1 is enriched in HSCs and multipotent progenitors, and in erythroid and megakaryocytic lineages9,10,11, consistent with roles for this factor in adult haematopoiesis. Here we assess by conditional gene targeting whether SCL/tal-1 is required continuously for the identity and function of HSCs. We find that SCL/tal-1 is dispensable for HSC engraftment, self-renewal and differentiation into myeloid and lymphoid lineages; however, the proper differentiation of erythroid and megakaryocytic precursors is dependent on SCL/tal-1. Thus, SCL/tal-1 is essential for the genesis of HSCs, but its continued expression is not essential for HSC functions. These findings contrast with lineage choice mechanisms, in which the identity of haematopoietic lineages requires continuous transcription factor expression12,13.

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Figure 1: Inducible inactivation of the SCL/tal-1 locus in vivo.
Figure 2: Continuing lymphopoiesis and myelopoiesis in the absence of SCL/tal-1.
Figure 3: Requirement for SCL in erythroid and megakaryocytic differentiation in vitro.
Figure 4: Requirement for SCL in erythroblast maturation in the bone marrow.
Figure 5: Haematopoietic stem cell function in the absence of SCL/tal-1.

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Acknowledgements

We thank D. Traver for discussions; J. Dailey and S. Lazo-Kallanian for cell sorting; K. Rajewsky for MxCre mice; and A. Williams and S. Galusha for assistance in generating the conditional SCL/tal-1 strain. H.K.A.M. received support from the Finnish Cultural Foundation and the Academy of Finland. This work was supported in part by a grant from the NIH to S.H.O., who is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to Stuart H. Orkin.

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Mikkola, H., Klintman, J., Yang, H. et al. Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene. Nature 421, 547–551 (2003). https://doi.org/10.1038/nature01345

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