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

Abstract

SummaryThe 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.

Regulation of blood cell transdifferentiation by oxygen sensing neurons

“…Transdifferentiation is known in many species including vertebrates (Cieslar-Pobuda et al, 2017;Reid and Tursun, 2018), but in the blood cell system transdifferentiation has for the most part only been studied in vitro and by experimental manipulations. For example, C/EBP (CCAAT/enhancerbinding protein) transcription factors drive transdifferentiation of vertebrate B cells into macrophages (Xie et al, 2004) (Di Tullio et al, 2011), force B lymphoma and leukemia cell lines to transdifferentiate into macrophages (Rapino et al, 2013), and facilitate B cell transdifferentiation to Granulocyte-Macrophage Precursors (Cirovic et al, 2017). Similarly, manipulation of key transcription factors such as FLI1 and ERG result in transdifferentiation of erythroblasts to megakaryocytes (Siripin et al, 2015), and deletion of the BAF Chromatin Remodeling Complex Subunit Bcl11b triggers T cell transition to NK cells (Li et al, 2010).…”

Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

“…Once again, many of the detected associations recover known aspects of histone mark biology, as expected. For example, the TFs most strongly associated to H3K4me1 included PU.1 and CEBPB, both of which act to increase H3K4me1 in blood cells and play strong roles in differentiation of those cell types [36][37][38][39] , and binding of MYC, which has a known role as a chromatin modifier 40,41 , including of H3K4 methylation 42 . We also observed a strong positive association between H3K27ac and CREB1, a binding partner of the lysine acetyltransferase EP300, as well as a weaker positive association for EP300 itself, matching the well-documented role of both factors in creation and maintenance of this mark 43,44 .…”

Transcriptional and Microenvironmental Regulation of Lineage Ambiguity in Leukemia

“…Purified B-ALL blasts exhibited myeloid cell marker expression and phagocytotic phenotypes upon stimulation by IL-3, M-CSF, and GM-CSF. The reprogrammed macrophage-like cells (termed MLCs) had increased expression of myeloid master regulators C/ebp-α and Pu.1, and corresponding overexpression of C/ebp-α and Pu.1 significantly induced myeloid reprogramming, suggesting that the myeloid cytokines and myeloid transcription factors cooperate to confer a myeloid cell fate to B-ALL, consistent with the ability of these two transcription factors to confer a myeloid fate to lymphocytes ( 11 , 12 , 14 ). Interestingly, although the original B-ALL cells that failed to reprogram into MLCs had the ability to cause B-ALL in recipient mice upon xenotransplantation, the reprogrammed MLCs had negligible ability to engraft.…”

“…Among these are the lineage-specific master regulator transcription factors, such as Pu.1 (also known as Spi-1; spleen focus forming virus proviral integration oncogene 1), C/ebp-α, Gata1, Pax5, and Ikaros (Figure 1 ). Pu.1 and C/ebp-α are master regulators of the myeloid cell fate, and not only do these transcription factors promote myeloid differentiation of progenitor cells ( 10 ) but also ectopic expression of these transcription factors confer a myeloid cell fate to cells of other lineages, such as T-cells, B-cells, or fibroblasts ( 11 – 14 ). Gata1 is a master regulator of erythroid cell fate that is required and sufficient to confer the erythroid fate.…”