Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor.
Sanchez Castillo, Manuel
Norddahl, Gudmundur L
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Wahlestedt, M., Ladopoulos, V., Hidalgo, I., Sanchez Castillo, M., Hannah, R., Säwén, P., Wan, H., et al. (2017). Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor.. Cell reports, 21 (8), 2251-2263. https://doi.org/10.1016/j.celrep.2017.10.112
Hematopoiesis commences with a gradual restriction in lineage potential of multipotent stem/progenitor cells, but the underlying molecular events of this remain incompletely understood. We here identify robust expression of the transcription factor Hepatic Leukemia Factor (Hlf) in multipotent hematopoietic progenitors, which is rapidly lost with differentiation. Prolonged Hlf expression reveals it as a strong negative regulator of lymphoid development and results in a pronounced and reversible differentiation block in the B-cell lineage while remaining compatible with myeloid fates. Reciprocally, we observe rapid lymphoid commitment upon reduction of Hlf activity. These phenotypes result from Hlf-binding to active enhancers of myeloid-competent cells, induction of myeloid-affiliated transcription and ablation of lymphoid gene programs, with Hlf induction of Nuclear Factor I C (Nfic) as a functionally relevant target gene. Collectively, we establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny.
Hematopoietic Stem Cells, Myeloid Cells, Multipotent Stem Cells, Animals, Mice, Leukemia, Cell Differentiation, Hematopoiesis, Lymphopoiesis, Gene Expression Regulation, Cell Lineage, Basic-Leucine Zipper Transcription Factors
This work was generously supported by project grants to DB from the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Pediatric Leukemia Foundation, Knut and Alice Wallenberg foundation and an ERC consolidator grant (615068). We would like to acknowledge Tom Serwold, Ewa Sitnicka and Mikael Sigvardsson for valuable scientific discussions, and Eva Erlandsson and Gerd Sten for expert technical assistance. The Genome Technology Access Center, Department of Genetics, Washington University School of Medicine, assisted with genomic analysis and is partially supported by NCI Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center, ICTS/CTSA Grant UL1TR000448 from the National Center for Research Resources (NCRR, a component of the NIH), and the NIH Roadmap for Medical Research.
Leukaemia & Lymphoma Research (12029)
Cancer Research UK (21762)
National Institutes of Health (NIH) (via Pennsylvania State University) (R24DK106766)
External DOI: https://doi.org/10.1016/j.celrep.2017.10.112
This record's URL: https://www.repository.cam.ac.uk/handle/1810/277563
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: http://creativecommons.org/licenses/by-nc-nd/4.0/
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