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

• Published in: bioRxiv
• Main Authors: Jacobson, Elsie C, Jain, Lekha, Vickers, Mark H, Olins, Ada L, Olins, Donald E, Perry, Jo K, O'sullivan, Justin
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 15.05.2019
• Subjects: Acute myeloid leukemia; Cell cycle; Cell death; Cell survival; Gene expression; Granulocytes; Immunomodulation; Leukemia; Leukocytes (granulocytic); Macrophages; Myeloid leukemia; Promyeloid leukemia; Retinoic acid; Ribonucleic acid; RNA; Transcription; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• DOI: 10.1101/471789

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, comparisons with gene expression changes associated with differentiation indicated that TNF-α treatment of granulocytes shifts the transcriptome towards 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. Footnotes * A subset of RNA-seq results (TNF, VCAM1, CDK1) have been validated with RT-qPCR in an independent set of samples.