Stepwise reprogramming of B cells into macrophages.
Starting with multipotent progenitors, hematopoietic lineages are specified by lineage-restricted transcription factors. The transcription factors that determine the decision between lymphoid and myeloid cell fates, and the underlying mechanisms, remain largely unknown. Here, we report that enforced expression of C/EBPalpha and C/EBPbeta in differentiated B cells leads to their rapid and efficient reprogramming into macrophages. C/EBPs induce these changes by inhibiting the B cell commitment transcription factor Pax5, leading to the downregulation of its target CD19, and synergizing with endogenous PU.1, an ETS family factor, leading to the upregulation of its target Mac-1 and other myeloid markers. The two processes can be uncoupled, since, in PU.1-deficient pre-B cells, C/EBPs induce CD19 downregulation but not Mac-1 activation. Our observations indicate that C/EBPalpha and beta remodel the transcription network of B cells into that of macrophages through a series of parallel and sequential changes that require endogenous PU.1.
Xie
Huafeng
H
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine Cancer Research Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Ye
Min
M
Feng
Ru
R
Graf
Thomas
T
D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D006689:Hodgkin Disease / Q000209:etiology; D006801:Humans; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D051757:PAX5 Transcription Factor; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D018941:Antigens, CD19; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D016177:Macrophage-1 Antigen; D051757:PAX5 Transcription Factor; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C497281:PAX5 protein, human; C497282:Pax5 protein, mouse