MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs

Leukemia. 2017 Dec;31(12):2780-2790. doi: 10.1038/leu.2017.163. Epub 2017 May 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / genetics*
  • B7-H1 Antigen / metabolism
  • Cell Line, Tumor
  • Gene Expression Regulation, Leukemic*
  • Humans
  • Immunomodulation / genetics
  • Mice
  • MicroRNAs / genetics*
  • Mucin-1 / genetics
  • Mucin-1 / metabolism*
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism
  • Transcriptional Activation
  • Up-Regulation


  • B7-H1 Antigen
  • CD274 protein, human
  • MicroRNAs
  • Mucin-1
  • Proto-Oncogene Proteins c-jun
  • Ribonuclease III