Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma
Proceedings of the National Academy of Sciences
National Academy of Sciences
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Rui, L., Drennan, A., Ceribelli, M., Zhu, F., Wright, G., Huang, D., Xiao, W., et al. (2016). Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma. Proceedings of the National Academy of Sciences, 113 (46), E7260-E7267. https://doi.org/10.1073/pnas.1610970113
Janus kinases (JAKs) classically signal by activating STAT transcription factors but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B-cell lymphomas (DLBCLs), JAK signaling is a feature of the activated B-cell (ABC) subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin, or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells. Whereas STAT3 contributed to the survival of ABC DLBCL cell lines, forced STAT3 activity could not protect these cells from death following JAK1 inhibition, suggesting epigenetic JAK1 action. JAK1 regulated the expression of nearly 3,000 genes in ABC DLBCL cells, and the chromatin surrounding many of these genes was modified by H3Y41-P marks that were diminished by JAK1 inhibition. These JAK1 epigenetic target genes encode important regulators of ABC DLBCL proliferation and survival, including IRF4, MYD88, and MYC. A small molecule JAK1 inhibitor cooperated with the BTK inhibitor ibrutinib in reducing IRF4 levels and acted synergistically to kill ABC DLBCL cells, suggesting that this combination should be evaluated in clinical trials.
JAK1, epigenetics, histone modification, lymphoma, oncogene
This research was supported by the Intramural Research Program of the NIH National Cancer Institute, the University of Wisconsin–Madison (UW–Madison) start-up funds, KL2 Scholar Awards UL1TR0000427 and KL2TR000428, the National Cancer Institute Grant 1R01 CA187299 (to L.R.), and the UW–Madison T32 Hematology Training Award T32 HL07899 (to A.C.D.).
External DOI: https://doi.org/10.1073/pnas.1610970113
This record's URL: https://www.repository.cam.ac.uk/handle/1810/261546