MUC1 Is a Potential Target for the Treatment of Acute Myeloid Leukemia Stem Cells

Stroopinsky, Dina; Rosenblatt, Jacalyn; Ito, Keisuke; Mills, Heidi; Li, Yin; Rajabi, Hasan; Vasir, Baldev; Kufe, Turner; Luptakova, Katarina; Arnason, Jon; Nardella, Caterina; Levine, James D.; Joyce, Robin; Galinsky, Ilene; Reiter, Yoram; Stone, Richard; Pandolfi, Pier Paolo; Küfe, Donald; Avigan, David

doi:10.1158/0008-5472.can-13-0677

Cited by 53 publications

(57 citation statements)

References 34 publications

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“…14,15 Notably, treatment of MM and AML cells with MUC1-C inhibitors has been associated with increases in ROS and thereby cell death in vitro and in xenograft models. [15][16][17] Here, we demonstrate that MUC1 is overexpressed in CTCL cell lines in comparison with B-cell lymphoma cell lines and normal T cells. Investigation of primary CTCL cells confirmed high levels of MUC1 expression in the malignant T-cell population, in contrast to T cells from normal individuals.…”

Section: Introductionmentioning

confidence: 61%

“…16,17 Briefly, cells were incubated with monoclonal antibody (mAb) DF3 (anti-MUC1-N) or a control mouse immunoglobulin (Ig) G1 for 30 minutes, followed by secondary labeling of the cells with phycoerythrin-conjugated goat anti-mouse IgG for an additional 30 minutes. Stained cells were analyzed by flow cytometry using FACScan and CellQuest Pro software (BD Biosciences).…”

Section: Detection Of Muc1 Expression By Flow Cytometrymentioning

confidence: 99%

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Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma

Jain

Stroopinsky

et al. 2015

Blood

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• MUC1-C oncoprotein contributes toward maintenance of redox balance in CTCL.• Targeting the MUC1-C oncoprotein in CTCL cells induces ROS-mediated death highlighting its potential as an effective strategy.Cutaneous T-cell lymphoma (CTCL) is an aggressive neoplasm with limited treatments for patients with advanced disease. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein plays a critical role in regulating cell proliferation, apoptosis, and protection from cytotoxic injury mediated by reactive oxygen species (ROS). Although CTCL cells exhibit resistance to ROS-induced apoptosis, the expression and functional significance of MUC1 in CTCL have not been previously investigated. Present studies demonstrate that MUC1-C is overexpressed in CTCL cell lines and primary CTCL cells but is absent in resting T cells from healthy donors and B-cell lymphoma cells. We have developed a cell-penetrating peptide that disrupts homodimerization of the MUC1-C subunit necessary for its nuclear translocation and downstream signaling. We show that treatment of CTCL cells with the MUC1-C inhibitor is associated with downregulation of the p53-inducible regulator of glycolysis and apoptosis and decreases in reduced NAD phosphate and glutathione levels. In concert with these results, targeting MUC1-C in CTCL cells increased ROS and, in turn, induced ROS-mediated late apoptosis/necrosis. Targeting MUC1-C in CTCL tumor xenograft models demonstrated significant decreases in disease burden. These findings indicate that MUC1-C maintains redox balance in CTCL cells and is thereby a novel target for the treatment of patients with CTCL. (Blood. 2015;126(3):354-362)

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Section: Introductionmentioning

confidence: 61%

Section: Detection Of Muc1 Expression By Flow Cytometrymentioning

confidence: 99%

Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma

Jain

Stroopinsky

et al. 2015

Blood

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“…25,26 Significantly, treatment of AML cell lines and blasts with MUC1-C inhibitors is associated with growth inhibition and death induction. 19,27 These findings provided support for the dependence of AML cells on MUC1-C for their survival.…”

Section: Introductionmentioning

confidence: 63%

“…MUC1 is expressed in most if not all primary AML cells and cell lines. 19 Indeed, recent work has shown that AML stem/progenitor cells from 26 patients all express MUC1. 19 By contrast, normal hematopoietic stem cells express low to undetectable MUC1 levels.…”

Section: Targeting Muc1-c Suppresses Growth Of Primary Aml Cellsmentioning

confidence: 99%

“…14 Mucin 1 (MUC1) is a heterodimeric protein that is normally expressed at the apical borders of epithelial cells. 15,16 Intriguingly, MUC1 is aberrantly expressed in AML blasts 17,18 and in AML stem cells 19 ; however, the functional role of MUC1 in AML is unknown. Of importance to understanding its function, MUC1 consists of 2 subunits that form a stable complex at the cell surface.…”

Section: Introductionmentioning

confidence: 99%

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MUC1-C oncoprotein promotes FLT3 receptor activation in acute myeloid leukemia cells

Liu

Stroopinsky

et al. 2014

Blood

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• The MUC1-C oncoprotein is aberrantly expressed in AML cells and contributes to activation of the mutant FLT3 receptor.• Targeting MUC1-C thus inhibits FLT3 signaling and represents a potential approach for AML cells resistant to FLT3 inhibitors.Blasts from approximately one-third of patients with acute myeloid leukemia (AML) harbor activating mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase that confer a poor prognosis. The Mucin 1-C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in AML blasts and stem cells; however, there is no known interaction between MUC1-C and FLT3. The present studies demonstrate that MUC1-C associates with wild-type and mutant FLT3 in AML cells. Targeting

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Localized fluorescent imaging of multiple proteins on individual extracellular vesicles using rolling circle amplification for cancer diagnosis

Zhang

Shi

Zhang

et al. 2020

J of Extracellular Vesicle

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Extracellular vesicles (EV) have attracted increasing attention as tumour biomarkers due to their unique biological property. However, conventional methods for EV analysis are mainly based on bulk measurements, which masks the EV‐to‐EV heterogeneity in tumour diagnosis and classification. Herein, a localized fluorescent imaging method (termed Digital Profiling of Proteins on Individual EV, DPPIE) was developed for analysis of multiple proteins on individual EV. In this assay, an anti‐CD9 antibody engineered biochip was used to capture EV from clinical plasma sample. Then the captured EV was specifically recognized by multiple DNA aptamers (CD63/EpCAM/MUC1), followed by rolling circle amplification to generate localized fluorescent signals. By‐analyzing the heterogeneity of individual EV, we found that the high‐dimensional data collected from each individual EV would provide more precise information than bulk measurement (ELISA) and the percent of CD63/EpCAM/MUC1‐triple‐positive EV in breast cancer patients was significantly higher than that of healthy donors, and this method can achieve an overall accuracy of 91%. Moreover, using DPPIE, we are able to distinguish the EV between lung adenocarcinoma and lung squamous carcinoma patients. This individual EV heterogeneity analysis strategy provides a new way for digging more information on EV to achieve multi‐cancer diagnosis and classification.

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MUC1 Is a Potential Target for the Treatment of Acute Myeloid Leukemia Stem Cells

Cited by 53 publications

References 34 publications

Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma

Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma

MUC1-C oncoprotein promotes FLT3 receptor activation in acute myeloid leukemia cells

Localized fluorescent imaging of multiple proteins on individual extracellular vesicles using rolling circle amplification for cancer diagnosis

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