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bioRxiv · 10.1101/471789

TNF-α differentially regulates cell cycle genes in promyelocytic and granulocytic HL-60/S4 cells

Jacobson, E. C.·Perry, J. K.·Vickers, M. H.·Olins, A. L.·Olins, D. E.·O'Sullivan, J.
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Abstract

Tumor necrosis factor alpha (TNF-) is a potent cytokine involved in systemic inflammation and immune modulation. Signaling responses that involve TNF- are context dependent and capable of stimulating pathways promoting both cell death and survival. TNF- treatment has been investigated as part of a combined therapy for acute myeloid leukemia due to its modifying effects on all-trans retinoic acid (ATRA) mediated differentiation into granulocytes.\n\nTo investigate the interaction between cellular differentiation and TNF-, we performed RNA-sequencing on two forms of the human HL-60/S4 promyelocytic leukemia cell line treated with TNF-. The ATRA-differentiated granulocytic form of HL-60/S4 cells had an enhanced transcriptional response to TNF- treatment compared to the undifferentiated promyelocytes. The observed TNF- responses included differential expression of cell cycle gene sets, which were generally upregulated in TNF- treated promyelocytes, and downregulated in TNF- treated granulocytes. This is consistent with TNF- induced cell cycle repression in granulocytes and cell cycle progression in promyelocytes. Moreover, comparisons with gene expression changes associated with differentiation indicated that TNF- treatment of granulocytes shifts the transcriptome towards that of a macrophage.\n\nWe conclude that TNF- treatment promotes a divergent transcriptional program in promyelocytes and granulocytes. TNF- promotes cell cycle associated gene expression in promyelocytes. In contrast, TNF- stimulated granulocytes have reduced cell cycle gene expression, and a macrophage-like transcriptional program.

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Jacobson, E. C., Perry, J. K., Vickers, M. H., Olins, A. L., Olins, D. E., O'Sullivan, J.. 2018-11-19. TNF-α differentially regulates cell cycle genes in promyelocytic and granulocytic HL-60/S4 cells. https://doi.org/10.1101/471789

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