Pyzer, Athalia RachelStroopinsky, DinaRosenblatt, JacalynAnastasiadou, EleniRajabi, HasanWashington, AbigailTagde, AshujitChu, Jen-HwaColl, MaxwellJiao, ALTsai, LTTenen, DECole, Leandra SamanthaPalmer, KristenEphraim, ALeaf, Rebecca KarpNahas, MyrnaApel, ArieBar-Natan, MJain, SalviaMcMasters, MalgorzataMendez, LourdesArnason, JonRaby, BenjaminSlack, FrankKufe, DonaldAvigan, David2017-09-272017Pyzer, 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.2017.163.0887-6924http://nrs.harvard.edu/urn-3:HUL.InstRepos:33956870The 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.en-USleukemiaMUC1PD-L1oncogenemicroRNAimmune microenvironmentJournal Article2017-05-252017-12-2810.1038/leu.2017.163