Hematopoietic stem cells give rise to a succession of intermediate progeny that ultimately differentiate into blood cells of all lineages. As they mature, it was generally thought that progenitor cells would become progressively restricted to a single fate. However, some studies have hinted that cells committed to a particular lineage might be more plastic than originally thought.1,2 Further supporting this notion, a recent study by Xie et al. provides strong evidence that B cell progenitors, and even some mature B cells, can be induced to adopt the gene expression patterns, morphology, and functional activities of macrophages.3
C/EBP alpha and C/EBP beta are bZip family transcription factors with putative roles in myelopoiesis.4 Using a retroviral approach, the authors overexpressed C/EBPa in CD19+ mouse bone marrow B cell progenitors. This treatment resulted in about 60% of the cells downregulating B cell-restricted genes (CD19, Rag1, B220, Mb-1, EBF, Pax5, and others) and upregulating macrophage-restricted genes (MAC-1, Fc gamma RIII, Fc gamma R1, M-CSF R, PU.1, and others). Remarkably, even mature antibody-expressing B cells isolated from spleen were susceptible to reprogramming, albeit at a lower efficiency of 31%. When the expression of CD19 and MAC-1 were followed over time, individual cells expressing both lineage markers were found at intermediate stages of development (Figure 1). Reprogrammed B cells not only expressed macrophage markers, but also adopted the larger morphology of macrophages and were phagocytic.
What mechanism underlies the transformation of a B cell into a macrophage? PU.1 is a key transcription factor in myeloid development, and the authors showed that it is upregulated in reprogrammed B cells.4 If PU.1 and C/EBP alpha are co-overexpressed, the number of reprogrammed B cells increases from 60% to 92%. Since PU.1 had no effect by itself, it was concluded that the two transcription factors were working in synergy, and that the levels of PU.1 might dictate whether a B cell was capable of being reprogrammed. A closer look at the effects of PU.1 revealed that it was critical for the upregulation of MAC-1, but not the downregulation of CD19. What causes CD19 downregulation? The authors show that C/EBP alpha overexpression inhibits B cell transcription factor Pax5 activity on the CD19 promoter.
|Figure 1. When transfected with C/EBPa, a subset of B cell progenitors lose the B cell marker CD19, and acquire macrophage functions and the macrophage marker MAC-1. This results from C/EBPa acting in synergy with the transcription factor PU.1 leading to MAC-1 upregulation, and the inhibition of CD19-activation by Pax5.
It appears that the upregulation of a single transcription factor can set in motion a series of events that can transform a B cell into a macrophage. It is unclear whether such processes might occur naturally. However, Hodgkin's lymphoma cells express myeloid markers; and although nearly devoid of B cell markers, they do exhibit IgH VDJ rearrangements suggesting that they might have a link to the B cell lineage.6,7 Consequently, it is plausible that processes similar to the described B cell to macrophage conversion could take place under certain pathological conditions.3
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- Iwasaki, H. et al. (2003) Immunity 19:451.
- Xie, H. et al. (2004) Cell 117:663.
- Friedman, A.D. et al. (2002) Int. J. Hematol. 75:466.
- Lee, B.L. & C. Murre (2001) Curr. Opin. Immunol. 13:180.
- Küppers, R. et al. (2002) Ann. Oncol. 13:11.
- Mirro, J. et al. (1986) Blood 68:597.