C/EBP-Induced Transdifferentiation Reveals Granulocyte-Macrophage Precursor-like Plasticity of B Cells

• Published in: Stem cell reports Vol. 8; no. 2; pp. 346 - 359
• Main Authors: Cirovic, Branko, Schönheit, Jörg, Kowenz-Leutz, Elisabeth, Ivanovska, Jelena, Klement, Christine, Pronina, Nina, Bégay, Valérie, Leutz, Achim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-02-2017; Elsevier
• Subjects: Animals; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Cell Differentiation; Cell Lineage - genetics; Cell Proliferation; Cell Transdifferentiation - genetics; differentiation; Gene Dosage; Granulocyte-Macrophage Progenitor Cells - cytology; Granulocyte-Macrophage Progenitor Cells - metabolism; hematopoiesis; Hematopoiesis - genetics; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; leukemia; lineage switch; Mice; Multigene Family; Phenotype; progenitor; stem cell; leukemia; progenitor; hematopoiesis; differentiation; stem cell; lineage switch
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2016.12.015

The lymphoid-myeloid transdifferentiation potentials of members of the C/EBP family (C/EBPα, β, δ, and ε) were compared in v-Abl-immortalized primary B cells. Conversion of B cells to macrophages was readily induced by the ectopic expression of any C/EBP, and enhanced by endogenous C/EBPα and β activation. High transgene expression of C/EBPβ or C/EBPε, but not of C/EBPα or C/EBPδ, also induced the formation of granulocytes. Granulocytes and macrophages emerged in a mutually exclusive manner. C/EBPβ-expressing B cells produced granulocyte-macrophage progenitor (GMP)-like progenitors when subjected to selective pressure to eliminate lymphoid cells. The GMP-like progenitors remained self-renewing and cytokine-independent, and continuously produced macrophages and granulocytes. In addition to their suitability to study myelomonocytic lineage bifurcation, lineage-switched GMP-like progenitors could reflect the features of the lympho-myeloid lineage switch observed in leukemic progression.
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•Transactivating C/EBP family members transdifferentiate B cells to myeloid cells•C/EBPβ or C/EBPε transdifferentiate B cells to macrophages and granulocytes•Transgene dosage determines granulocyte versus macrophage cell-type outcome•C/EBP-mediated B cell conversion elicits GMP-like potential
In this article, Leutz and colleagues assessed the transdifferentiation potential of four C/EBP transcription factors in B cells. C/EBPβ and C/EBPε stimulated the formation of macrophage and granulocyte-like cells. Transdifferentiation involved endogenous C/EBP activation. High transgene dosage promoted granulocyte versus macrophage outcome. C/EBPβ also elicited a stable GMP-like phenotype that could serve as a model to study cell-fate decision.