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Bar-Natan, M

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Bar-Natan

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Bar-Natan, M
Author's Publications: search.filters.isAuthorOfPublication.3d0223f0-2164-4984-bc7a-8cf07b04d2a8

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    STAT signaling in the pathogenesis and treatment of myeloid malignancies
    (Landes Bioscience, 2012) Bar-Natan, M; Nelson, Erik A.; Xiang, Michael; Frank, David
    STAT transcription factors play a critical role in mediating the effects of cytokines on myeloid cells. As STAT target genes control key processes such as survival, proliferation and self-renewal, it is not surprising that constitutive activation of STATs, particularly STAT3 and STAT5, are common events in many myeloid tumors. STATs are activated both by mutant tyrosine kinases as well as other pathogenic events, and continued activation of STATs is common in the setting of resistance to kinase inhibitors. Thus, the targeting of STATs, alone or in combination with other drugs, will likely have increasing importance for cancer therapy.
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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.