C/EBPα Induces Highly Efficient Macrophage Transdifferentiation of B Lymphoma and Leukemia Cell Lines and Impairs Their Tumorigenicity

• Published in: Cell reports (Cambridge) 2013-04, Vol.3 (4), p.1153-1163
• Main Authors: Rapino, Francesca, Robles, Eloy F., Richter-Larrea, Jose A., Kallin, Eric M., Martinez-Climent, Jose A., Graf, Thomas
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Hormonal - therapeutic use; Antineoplastic Agents, Hormonal - toxicity; CCAAT-Enhancer-Binding Protein-alpha - metabolism; Cell Line, Tumor; Cell Lineage; Cell Transdifferentiation - drug effects; Humans; Leukemia - metabolism; Leukemia - pathology; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - mortality; Macrophages - cytology; Macrophages - metabolism; Mice; Phagocytosis; Tamoxifen - therapeutic use; Tamoxifen - toxicity; Transcriptome; Transplantation, Heterologous
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.03.003

Earlier work demonstrated that the transcription factor C/EBPα can convert immature and mature murine B lineage cells into functional macrophages. Testing >20 human lymphoma and leukemia B cell lines, we found that most can be transdifferentiated at least partially into macrophage-like cells, provided that C/EBPα is expressed at sufficiently high levels. A tamoxifen-inducible subclone of the Seraphina Burkitt lymphoma line, expressing C/EBPαER, could be efficiently converted into phagocytic and quiescent cells with a transcriptome resembling normal macrophages. The converted cells retained their phenotype even when C/EBPα was inactivated, a hallmark of cell reprogramming. Interestingly, C/EBPα induction also impaired the cells’ tumorigenicity. Likewise, C/EBPα efficiently converted a lymphoblastic leukemia B cell line into macrophage-like cells, again dramatically impairing their tumorigenicity. Our experiments show that human cancer cells can be induced by C/EBPα to transdifferentiate into seemingly normal cells at high frequencies and provide a proof of principle for a potential new therapeutic strategy for treating B cell malignancies. [Display omitted] ► C/EBPα converts selected human lymphoma and leukemia B cell lines into macrophages ► During transdifferentiation, cells become phagocytic and quiescent ► Cells retain their macrophage phenotype even after withdrawal of the C/EBPα inducer ► C/EBPα impairs the tumorigenicity of responsive lymphoma/leukemia cells C/EBPα acts as a tumor suppressor in a group of acute myeloid leukemia and induces the efficient transdifferentiation of B cells into macrophages. Martinez-Climent, Graf, and colleagues now show that C/EBPα can convert selected human B cell lymphoma/leukemia cell lines into quiescent macrophages, capable of phagocytosing bacteria and yeast. In addition, this conversion, which occurs at high efficiencies, impairs the cells’ tumor-forming capacity, providing a proof of principle that lymphoid-to-myeloid lineage transdifferentiation may represent a therapeutic strategy for B cell neoplasms.