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Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor.

Published version
Peer-reviewed

Type

Article

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Authors

Wahlestedt, Martin 
Ladopoulos, Vasileios 
Hidalgo, Isabel 
Sanchez Castillo, Manuel 

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 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.

Description

Keywords

gene regulation, hematopoiesis, lineage commitment, lymphopoiesis, myelopoiesis, transcription factor, Animals, Basic-Leucine Zipper Transcription Factors, Cell Differentiation, Cell Lineage, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Leukemia, Lymphopoiesis, Mice, Multipotent Stem Cells, Myeloid Cells

Journal Title

Cell Rep

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

21

Publisher

Elsevier BV
Sponsorship
Leukaemia & Lymphoma Research (12029)
Medical Research Council (MC_PC_12009)
Cancer Research UK (21762)
National Institute of Diabetes and Digestive and Kidney Diseases (R24DK106766)
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.