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Activation of wnt/β-catenin signaling blocks monocyte–macrophage differentiation through antagonizing PU.1-targeted gene transcription

Leukemia volume 30, pages 2106–2109 (2016)Cite this article

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Tight regulation of canonical Wnt/β-catenin signaling is critical for maintaining normal hematopoiesis and its deregulation contributes to leukemia development.1 β-catenin, a central molecule in the canonical Wnt/β-catenin signaling pathway, acts as a nuclear transcriptional co-activator with the lymphoid enhancer factor/T-cell factor (LEF/TCF) family to stimulate transcription of various target genes.2 The intracellular level of β-catenin is controlled by a degradation complex consisting of Apc, Gsk-3β, Axin 1 and Ck-1.2 We found that loss of Apc leads to bone marrow failure due to exhaustion of hematopoietic stem and progenitor cells in mice.3 A marked decrease of Mac-1+Gr-1+ myeloid cells and rapid depletion of granulocyte–macrophage progenitors (GMPs), but not megakaryocyte–erythrocyte progenitors were observed in both Apc-null3 and transgenic mice with expression of stabilized β-catenin.4, 5 However, whether this decrease of myeloid cells is due to a blockage of differentiation of GMPs or the depletion of GMPs in vivo or both have not been defined.

Next, we determined whether activation of Wnt/β-catenin inhibits differentiation of human U973 cells exposed to PMA. We found that either expression of stabilized β-catenin (Supplementary Figure 4a) or knockdown Apc expression (Supplementary Figures 5a and b) significantly reduced the frequency of Mac-1+ and CD14+ cells of U937 cells after exposed to PMA (Supplementary Figure 4b; Figures 1e and f). Furthermore, stabilized β-catenin inhibits mRNA expression of CD14, Mac-1 and Csf1r genes induced by PMA in U937 cells, as determined by quantitative real time (qRT)-PCR (Figure 1g). As shown in Figure 1h, the morphological features associated with mature monocytes were observed in U937 cells expressing control vector but not β-cat-S33Y after PMA treatment for 48 h. These regulates suggest that activation of Wnt/β-catenin signaling inhibits PMA-induced monocyte/macrophage differentiation of U937 cells. Together, our studies demonstrate a negative role of β-catenin overexpression in monocyte/macrophage differentiation.

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Acknowledgements

We would like to acknowledge the funding support from by the National Institute of Health grants RO1 CA140979 (to ZQ) and the China Scholarship Council (to WJ).

Author contributions

ZQ, YS and WJ: study design; ZQ, YS, WJ, YH, XQ and JL: acquisition of data, analysis and interpretation of data; ZQ, HO, YS, WJ and YH: manuscript preparation.

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  1. Y Sheng and W Ju: These authors contributed equally to this work.

Authors and Affiliations

  1. College of Public Health, Jilin University, Jilin, China

    W Ju & J Li

  2. Department of Medicine and Cancer Center, University of Illinois at Chicago, Chicago, IL, USA

    Y Sheng, W Ju, H Ozer & Z Qian

  3. Department of Medicine, Section of Gastroenterology, The University of Chicago, Chicago, IL, USA

    Y Huang

  4. Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, China

    X Qiao

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  1. Y Sheng
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Correspondence to J Li or Z Qian.

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Supplementary Information accompanies this paper on the Leukemia website

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Sheng, Y., Ju, W., Huang, Y. et al. Activation of wnt/β-catenin signaling blocks monocyte–macrophage differentiation through antagonizing PU.1-targeted gene transcription. Leukemia 30, 2106–2109 (2016). https://doi.org/10.1038/leu.2016.146

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