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Cole, Leandra Samantha

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Leandra Samantha

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Cole, Leandra Samantha

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    MUC1 Inhibition Leads to Decrease in PD-L1 Levels via Up-Regulation of miRNAs
    (Springer Nature, 2017) Pyzer, Athalia Rachel; Stroopinsky, Dina; Rosenblatt, Jacalyn; Anastasiadou, Eleni; Rajabi, Hasan; 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; Apel, Arie; Bar-Natan, M; Jain, Salvia; McMasters, Malgorzata; Mendez, Lourdes; Arnason, Jon; Raby, Benjamin; Slack, Frank; Kufe, Donald; Avigan, David
    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.