Myeloid cell differentiation and macrophage function
A) Irf8-deficient mice display a myelo-proliferative disorder in the bone marrow. Here undifferentiated myeloid blasts accumulate and give rise to drastically increased numbers of granulocytes at the expense of monocytes/macrophages and dendritic cells. B) Conclusive model summarizing the regulatory circuitry between Irf8, Wnt signaling, and BCR-ABL. Scheme outlining the crosstalk between Wnt and IFN signaling in normal hematopoiesis and interference by BCR-ABL signaling. In normal hematopoiesis, activation of ß-catenin results in up-regulation of Irf8 (green line), which in turn limits oncogenic ß-catenin functions (red line). In leukemia BCR-ABL interferes with this cross talk by inhibiting Irf8 and by activating ß-catenin. Imatinib inhibits BCR-ABL and restores CML progression. Additional alterations at later stages of disease confer BCR-ABL–independent ß-catenin activation and Irf8 inhibition and thus cause Imatinib resistance.Please change the image description here
Myeloid cells, including granulocytes, macrophages and dendritic cells are phagocytic cells of the innate immune system. Phagocytes are responsible to sense and cleave away pathogens and to respond to diverse environmental signals. However, the multitude of invading pathogens on the one hand and the specificity to these pathogens on the other hand requires tremendous plasticity of the cell that is largely governed by the timely expression of transcription factors (Schönheit et al. J Mol Biol. 2014). Our lab is interested in how key transcription factors influence myeloid cell differentiation from haematopoietic stem cells under physiological as well as under pathological conditions.
The interferon regulatory factor 8 (Irf8) is a lineage determining factor that induces the formation of monocytes and macrophages at the expense of granulocytes and it is absolutely critical for the development of dendritic cell subsets. Recently our lab could show that the potential of Irf8 in driving dendritic cell development depends on binding of the haematopoietic master-regulator PU.1 to an Irf8-specific cis-enhancer (Schönheit et al. 2013 Cell Reports). Moreover, Irf8 gene expression pinpoints an initial progenitor stage at which dendritic cells separate from other myeloid lineages in the bone marrow. Interestingly, deletion of Irf8 results in a dendritic cell-to-granulocyte gene signature conversion that manifests as a phenotype that resembles chronic myeloid leukemia (CML) in humans. Using mouse genetics and a murine CML model, we observed crosstalk between Irf8 and β-Catenin, a member of the Wnt-pathway (Scheller et al. Nature Immunology 2006). Mechanistically we could recently show that leukemic cell proliferation depends on β-Catenin in Irf8-deficient animals (Scheller et al. J. Exp. Med. 2013). Strikingly, constitutive β-Catenin activation results in progression of CML into a more aggressive acute form of leukemia (AML) that is ultimately fatal. Interestingly, activated β-Catenin enhances a pre-existing Irf8-deficient gene signature, identifying β-Catenin as an amplifier of progression-specific gene regulation in the shift of CML to AML. Collectively, our data uncover Irf8 as a key lineage instructive transcription factor and a roadblock for β-Catenin-driven leukemia.