MDC Lab Coats

WNT-signaling, IRF8 & leukemogenesis

Myeloid cells, including granulocytes, macrophages and dendritic cells are phagocytic cells of the innate immune system. Phagocytes sense and eliminate pathogens and support development and regeneration. Adaptation to these various processes depend on cellular plasticity and tight regulation of genes that execute the respective functions.

The interferon regulatory factor 8 (Irf8) regulates the formation of monocytes and granulocytes and balances granulopoiesis with dendritic cell development. Deletion of the IRF8 gene in the mouse identified a progenitor that separates dendritic cells from other myeloid lineages. Interestingly, Irf8 deletion in the mouse gives rise to a phenotype that resembles chronic myelogenous leukemia (CML) in humans. In human CML, the BCR-ABL oncoprotein represses IRF8 and activates the WNT-signaling pathway. Experimental hematopoiesis in the mouse uncovered a crosstalk between the Irf8 and the Wnt- signaling pathway. Leukemic cell proliferation in Irf8-deficient animals depended on β-catenin. Strikingly, in IRF8 deficient mice, constitutive activation of β-catenin resulted in the progression of CML into aggressive acute leukemia (AML) by enhancing a pre-existing Irf8-deficient gene signature. Accordingly, dysregulated WNT-signaling acts as an amplifier of genes that shift CML to AML. Collectively, the data uncovered Irf8 as a key lineage instructive transcription factor and a roadblock for β-catenin-driven leukemia.

 

Scheller, M., Huelsken, J., Rosenbauer, F., Taketo, M.M., Birchmeier, W., Tenen, D.G., and Leutz, A. (2006). Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nature immunology 7, 1037-1047.

Scheller, M., Schonheit, J., Zimmermann, K., Leser, U., Rosenbauer, F., and Leutz, A. (2013). Cross talk between Wnt/beta-catenin and Irf8 in leukemia progression and drug resistance. The Journal of experimental medicine 210, 2239-2256.

Schonheit, J., Kuhl, C., Gebhardt, M.L., Klett, F.F., Riemke, P., Scheller, M., Huang, G., Naumann, R., Leutz, A., Stocking, C., et al. (2013). PU.1 level-directed chromatin structure remodeling at the Irf8 gene drives dendritic cell commitment. Cell reports 3, 1617-1628.