TNF-α Differentially Regulates Cell Cycle Genes in Promyelocytic and Granulocytic HL-60/S4 Cells

• Published in: G3 : genes - genomes - genetics Vol. 9; no. 8; pp. 2775 - 2786
• Main Authors: Jacobson, Elsie C, Jain, Lekha, Vickers, Mark H, Olins, Ada L, Olins, Donald E, Perry, Jo K, O'Sullivan, Justin M
• Format: Journal Article
• Language: English
• Published: United States Genetics Society of America 01.08.2019; Oxford University Press
• Subjects: Biomarkers; Cell cycle; Cytokine; Databases, Genetic; Differentiation; Gene Expression Profiling; Gene Expression Regulation, Leukemic - drug effects; Gene regulation; Genes, cdc; HL-60 Cells; Humans; Investigations; Leukemia; Leukemia, Promyelocytic, Acute - genetics; Transcriptome; Tumor Necrosis Factor-alpha - pharmacology; Differentiation; Gene regulation; Leukemia; Cell cycle; Cytokine
• ISSN: 2160-1836; 2160-1836
• DOI: 10.1534/g3.119.400361

Tumor necrosis factor alpha (TNF-α) is a potent cytokine involved in systemic inflammation and immune modulation. Signaling responses that involve TNF-α are context dependent and capable of stimulating pathways promoting both cell death and survival. TNF-α 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. To investigate the interaction between cellular differentiation and TNF-α, we performed RNA-sequencing on two forms of the human HL-60/S4 promyelocytic leukemia cell line treated with TNF-α. The ATRA-differentiated granulocytic form of HL-60/S4 cells had an enhanced transcriptional response to TNF-α treatment compared to the undifferentiated promyelocytes. The observed TNF-α responses included differential expression of cell cycle gene sets, which were generally upregulated in TNF-α treated promyelocytes, and downregulated in TNF-α treated granulocytes. This is consistent with TNF-α induced cell cycle repression in granulocytes and cell cycle progression in promyelocytes. Moreover, we found evidence that TNF-α treatment of granulocytes shifts the transcriptome toward that of a macrophage. We conclude that TNF-α treatment promotes a divergent transcriptional program in promyelocytes and granulocytes. TNF-α promotes cell cycle associated gene expression in promyelocytes. In contrast, TNF-α stimulated granulocytes have reduced cell cycle gene expression, and a macrophage-like transcriptional program.