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Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor

Wahlestedt, Martin LU ; Ladopoulos, Vasileios; Hidalgo, Isabel LU ; Sanchez Castillo, Manuel; Hannah, Rebecca; Säwén, Petter LU ; Wan, Haixia LU ; Dudenhöffer-Pfeifer, Monika LU ; Magnusson, Mattias LU and Norddahl, Gudmundur L. LU , et al. (2017) In Cell Reports 21(8). p.2251-2263
Abstract

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... (More)

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. Regulators of early blood cell formation are important in both health and disease. Wahlestedt et al. identify abrupt downregulation of the transcription factor Hlf during hematopoietic differentiation. Failure to downregulate Hlf leads to a drastically skewed output of mature blood cells, positioning Hlf as a critical regulator of hematopoiesis.

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@article{3012fa3c-8b95-4e58-b603-d7700cad932f,
  abstract     = {<p>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. Regulators of early blood cell formation are important in both health and disease. Wahlestedt et al. identify abrupt downregulation of the transcription factor Hlf during hematopoietic differentiation. Failure to downregulate Hlf leads to a drastically skewed output of mature blood cells, positioning Hlf as a critical regulator of hematopoiesis.</p>},
  author       = {Wahlestedt, Martin and Ladopoulos, Vasileios and Hidalgo, Isabel and Sanchez Castillo, Manuel and Hannah, Rebecca and Säwén, Petter and Wan, Haixia and Dudenhöffer-Pfeifer, Monika and Magnusson, Mattias and Norddahl, Gudmundur L. and Göttgens, Berthold and Bryder, David},
  issn         = {2211-1247},
  keyword      = {gene regulation,hematopoiesis,lineage commitment,lymphopoiesis,myelopoiesis,transcription factor},
  language     = {eng},
  month        = {11},
  number       = {8},
  pages        = {2251--2263},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor},
  url          = {http://dx.doi.org/10.1016/j.celrep.2017.10.112},
  volume       = {21},
  year         = {2017},
}