MUC1-C drives myeloid leukaemogenesis and resistance to treatment by a survivin-mediated mechanism.

Journal of Cellular and Molecular Medicine
D StroopinskyDavid Avigan

Abstract

Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with an unmet need for improved therapies. Responses to standard cytotoxic therapy in AML are often transient because of the emergence of chemotherapy-resistant disease. The MUC1-C oncoprotein governs critical pathways of tumorigenesis, including self-renewal and survival, and is aberrantly expressed in AML blasts and leukaemia stem cells (LSCs). However, a role for MUC1-C in linking leukaemogenesis and resistance to treatment has not been described. In this study, we demonstrate that MUC1-C overexpression is associated with increased leukaemia initiating capacity in an NSG mouse model. In concert with those results, MUC1-C silencing in multiple AML cell lines significantly reduced the establishment of AML in vivo. In addition, targeting MUC1-C with silencing or pharmacologic inhibition with GO-203 led to a decrease in active β-catenin levels and, in-turn, down-regulation of survivin, a critical mediator of leukaemia cell survival. Targeting MUC1-C was also associated with increased sensitivity of AML cells to Cytarabine (Ara-C) treatment by a survivin-dependent mechanism. Notably, low MUC1 and survivin gene expression were associated with better clinical ...Continue Reading

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Citations

Sep 10, 2019·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Stewart Sell, Zoran Ilic
Feb 2, 2019·International Journal of Molecular Sciences·Beatriz BallesterJulio Cortijo
Feb 18, 2021·Genes & Genomics·Xucai ZhengChenghao Jiang

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Datasets Mentioned

BETA
GSE1159

Methods Mentioned

BETA
nuclear translocation
PCR
flow cytometry
light microscopy
Assay
FACS
xenograft

Software Mentioned

CellQuest
bioconductor “
Kaluza
Diva
R
affy
CompuSyn

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