Open AccessMUC 1‐C drives myeloid leukaemogenesis and resistance to treatment by a survivin‐mediated mechanism
Author(s) -
Stroopinsky Dina,
Rajabi Hasan,
Nahas Myrna,
Rosenblatt Jacalyn,
Rahimian Maryam,
Pyzer Athalia,
Tagde Ashujit,
Kharbanda Akriti,
Jain Salvia,
Kufe Turner,
Leaf Rebecca K.,
Anastasiadou Eleni,
BarNatan Michal,
Orr Shira,
Coll Maxwell D.,
Palmer Kristen,
Ephraim Adam,
Cole Leandra,
Washington Abigail,
Kufe Donald,
Avigan David
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13662
Subject(s) - survivin , cancer research , gene silencing , cytarabine , myeloid , carcinogenesis , gene knockdown , biology , medicine , myeloid leukemia , immunology , cell culture , cancer , gene , biochemistry , genetics
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 MUC 1‐C oncoprotein governs critical pathways of tumorigenesis, including self‐renewal and survival, and is aberrantly expressed in AML blasts and leukaemia stem cells ( LSC s). However, a role for MUC 1‐C in linking leukaemogenesis and resistance to treatment has not been described. In this study, we demonstrate that MUC 1‐C overexpression is associated with increased leukaemia initiating capacity in an NSG mouse model. In concert with those results, MUC 1‐C silencing in multiple AML cell lines significantly reduced the establishment of AML in vivo. In addition, targeting MUC 1‐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 MUC 1‐C was also associated with increased sensitivity of AML cells to Cytarabine (Ara‐C) treatment by a survivin‐dependent mechanism. Notably, low MUC 1 and survivin gene expression were associated with better clinical outcomes in patients with AML . These findings emphasize the importance of MUC 1‐C to myeloid leukaemogenesis and resistance to treatment by driving survivin expression. Our findings also highlight the potential translational relevance of combining GO ‐203 with Ara‐C for the treatment of patients with AML .