Cell Reports (Nov 2017)

Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor

  • Martin Wahlestedt,
  • Vasileios Ladopoulos,
  • Isabel Hidalgo,
  • Manuel Sanchez Castillo,
  • Rebecca Hannah,
  • Petter Säwén,
  • Haixia Wan,
  • Monika Dudenhöffer-Pfeifer,
  • Mattias Magnusson,
  • Gudmundur L. Norddahl,
  • Berthold Göttgens,
  • David Bryder

DOI
https://doi.org/10.1016/j.celrep.2017.10.112
Journal volume & issue
Vol. 21, no. 8
pp. 2251 – 2263

Abstract

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A gradual restriction in lineage potential of multipotent stem/progenitor cells is a hallmark of adult hematopoiesis, but the underlying molecular events governing these processes remain incompletely understood. Here, we identified robust expression of the leukemia-associated transcription factor hepatic leukemia factor (Hlf) in normal multipotent hematopoietic progenitors, which was rapidly downregulated upon differentiation. Interference with its normal downregulation revealed Hlf as a strong negative regulator of lymphoid development, while remaining compatible with myeloid fates. Reciprocally, we observed rapid lymphoid commitment upon reduced Hlf activity. The arising phenotypes resulted from Hlf binding to active enhancers of myeloid-competent cells, transcriptional induction of myeloid, and ablation of lymphoid gene programs, with Hlf induction of nuclear factor I C (Nfic) as a functionally relevant target gene. Thereby, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis.

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