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Genetic alteration and direct regulation of BCL6 in B cell lymphoma. (A) A schematic of 3q DNA copy number gain (red) with GISTIC Q value corresponding to DNA copy number gain is shown. BCL6 copy gain is highlighted with arrow. (B) A circos plot shows translocations of BCL6 to a variety or partner genes. (C) BCL6 homodimer binds to its own promoter and negatively auto-regulate its expression. Mutations on the first non-coding exon of BCL6 disrupt this negative autoregulatory circuit by preventing BCL6 from binding its regulatory region. (D) MEF2B directly activates the transcription of BCL6 in normal GCB cells and mutations of MEF2B lead to deregulated expression of BCL6 in B cell lymphoma. (E) The BCL6 protein is regulated at the post-translational level by phosphorylation. Activated B cell receptor (BCR) signaling, DNA damage and SKP1–CUL1–Fbox protein (SCF) complex that contains the orphan F-box protein FBXO11 can all drive phosphorylation of BCL6 and its degradation by ubiquitin proteasome system.
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18 June 2019
Modeling the Hematopoietic Landscape
Geoffrey Brown
 and 
Rhodri Ceredig
Auto and promiscuous regulation of the expression of cytokin receptors. Macrophage-colony stimulating factor and granulocyte/ macrophage-colony stimulating factor/granulocyte-colony stimulating factor can instruct macrophage and neutrophil fates, respectively. Macrophage-colony stimulating factor receptor (M-CSFR) instruction of HSCs leads to expression of the transcription factor PU.1. PU.1 in turn regulates expression of the M-CSFR, the granulocyte/macrophage-colony stimulating factor receptor (GM-CSFR) and the granulocyte-colony stimulating factor receptor (G-CSFR). G-CSF receptor signaling increases the expression of C/EBPα that regulates the expression of the GM-CSFR and the G-CSFR. A complex interplay between transcription factors and the expression of cytokine receptors might underlie meta-stable bi-lineage cell states and allow HSCs that express the M-CSFR and cytokine stimulated to co-express G-CSFR “side step” to an adjacent pathway (Figure 1).

Some time ago, we proposed a continuum-like view of the lineages open to hematopoietic stem cells (HSCs); each HSC self-renews or chooses from the spectrum of all end-cell options and can then “merely” differentiate. Having selected a cell lineage, an individual HSC may still “step sideways” to an alternative, albeit closely related, fate: HSC and their progeny therefore remain versatile. The hematopoietic cytokines erythropoietin, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte/macrophage colony-stimulating factor and ligand for the fms-like tyrosine kinase 3 instruct cell lineage. Sub-populations of HSCs express each of the cytokine receptors that are positively auto-regulated upon cytokine binding. Many years ago, Waddington proposed that the epigenetic landscape played an important role in cell lineage choice. This landscape is dynamic and unstable especially regarding DNA methylation patterns across genomic DNA. This may underlie the receptor diversity of HSC and their decision-making.

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