Journal
BLOOD
Volume 136, Issue 22, Pages 2574-2587Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019004664
Keywords
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Funding
- MEYS [LM2015040, LM2018126, OP RDI CZ.1.05/2.1.00/19.0395]
- ERDF
- GACR (Czech Science Foundation) [17-02177S]
- GA UK fellowship from Charles University in Prague [1278217]
- EHA Short-Term Collaboration Award
- Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centres of Excellence initiative
- National Institutes of Health, National Cancer Institute [R35CA197697, CA66996]
- National Heart, Lung, and Blood Institute [HL131477]
- Cancer Science Institute of Singapore
- IMG [RVO 68378050]
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The canonical Wnt signaling pathway is mediated by interaction of beta-catenin with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors and subsequent transcription activation of Wnt-target genes. In the hematopoietic system, the function of the pathway has been mainly investigated by rather unspecific genetic manipulations of beta-catenin that yielded contradictory results. Here, we used a mouse expressing a truncated dominant negative form of the human TCF4 transcription factor (dnTCF4) that specifically abrogates beta-catenin-TCF/LEF interaction. Disruption of the beta-catenin-TCF/LEF interaction resulted in the accumulation of immature cells and reduced granulocytic differentiation. Mechanistically, dnTCF4 progenitors exhibited downregulation of the Csf3r gene, reduced granulocyte colony-stimulating factor (G-CSF) receptor levels, attenuation of downstream Stat3 phosphorylation after G-CSF treatment, and impaired G-CSF-mediated differentiation. Chromatin immunoprecipitation assays confirmed direct binding of TCF/LEF factors to the and enhancer of CSF3R. Inhibition of compromised activation of the emergency granulopoiesis program, which requires maintenance and expansion of myeloid progenitors. Consequently, dnTCF4 mice were more susceptible to Candida albicans infection and more sensitive to 5-fluorouracil-induced granulocytic regeneration. Importantly, genetic and chemical inhibition of beta-catenin-TCF/LEF signaling in human CD34(+) cells reduced granulocytic differentiation, whereas its activation enhanced myelopoiesis. Altogether, our data indicate that the beta-catenin-TCF/LEF complex directly regulates G-CSF receptor levels, and consequently controls proper differentiation of myeloid progenitors into granulocytes in steady-state and emergency granulopoiesis. Our results uncover a role for the beta-catenin signaling pathway in fine tuning the granulocytic production, opening venues for clinical intervention that require enhanced or reduced production of neutrophils.
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