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
Affiliations
Martin Wahlestedt
Lund University, Medical Faculty, Institution for Laboratory Medicine, Division of Molecular Hematology, Klinikgatan 26, BMC B12, 221 84 Lund, Sweden
Vasileios Ladopoulos
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Hills Road, Cambridge CB2 0XY, UK
Isabel Hidalgo
Lund University, Medical Faculty, Institution for Laboratory Medicine, Division of Molecular Hematology, Klinikgatan 26, BMC B12, 221 84 Lund, Sweden
Manuel Sanchez Castillo
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Hills Road, Cambridge CB2 0XY, UK
Rebecca Hannah
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Hills Road, Cambridge CB2 0XY, UK
Petter Säwén
Lund University, Medical Faculty, Institution for Laboratory Medicine, Division of Molecular Hematology, Klinikgatan 26, BMC B12, 221 84 Lund, Sweden
Haixia Wan
Lund University, Medical Faculty, Institution for Laboratory Medicine, Division of Molecular Hematology, Klinikgatan 26, BMC B12, 221 84 Lund, Sweden
Monika Dudenhöffer-Pfeifer
Lund University, Medical Faculty, Institution for Laboratory Medicine, Division of Molecular Hematology, Klinikgatan 26, BMC B12, 221 84 Lund, Sweden
Mattias Magnusson
Lund University, Lund Stem Cell Center, Molecular Medicine and Gene Therapy, Sölvegatan 17, 221 84 Lund, Sweden
Gudmundur L. Norddahl
Lund University, Medical Faculty, Institution for Laboratory Medicine, Division of Molecular Hematology, Klinikgatan 26, BMC B12, 221 84 Lund, Sweden
Berthold Göttgens
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Hills Road, Cambridge CB2 0XY, UK
David Bryder
Lund University, Medical Faculty, Institution for Laboratory Medicine, Division of Molecular Hematology, Klinikgatan 26, BMC B12, 221 84 Lund, Sweden
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.
