MUC1 Inhibition Leads to Decrease in PD-L1 Levels via Up-Regulation of miRNAs

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MUC1 Inhibition Leads to Decrease in PD-L1 Levels via Up-Regulation of miRNAs

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Title: MUC1 Inhibition Leads to Decrease in PD-L1 Levels via Up-Regulation of miRNAs
Author: Pyzer, Athalia Rachel; Stroopinsky, Dina; Rosenblatt, Jacalyn Mara; Anastasiadou, Eleni; Rajabi, Hasan Nabeel; Washington, Abigail; Tagde, Ashujit; Chu, Jen-Hwa; Coll, Maxwell; Jiao, AL; Tsai, LT; Tenen, DE; Cole, Leandra Samantha; Palmer, Kristen; Ephraim, A; Leaf, Rebecca Karp; Nahas, Myrna Rita; Apel, Arie; Bar-Natan, M; Jain, Salvia; McMasters, Malgorzata; Mendez, Lourdes Maria; Arnason, Jon E; Raby, Benjamin Alexander; Slack, Frank; Kufe, Donald William; Avigan, David E.

Note: Order does not necessarily reflect citation order of authors.

Citation: Pyzer, AR, D Stroopinsky, J Rosenblatt, E Anastasiadou, H Rajabi, A Washington, A Tagde, et al. 2017. “MUC1 Inhibition Leads to Decrease in PD-L1 Levels via Upregulation of miRNAs.” Leukemia (May 30). doi:10.1038/leu.2017.163.
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Abstract: The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in acute myeloid leukemia (AML), but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA-processing. MUC1 signaling decreased the expression of the microRNA-processing protein DICER, via the suppression of c-Jun activity. NanoString (Seattle, WA, USA) array of MUC1-silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia-specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T-cell-mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti-tumor immunity.
Published Version: doi:10.1038/leu.2017.163
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:33956870
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