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

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 outcomes in patients with AML. These findings emphasize the importance of MUC1‐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.

Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets

“…Similarly, these transmembrane mucins have previously been considered clinically relevant proteins that are aberrantly overexpressed in lung carcinogenesis [155]. In fact, Muc1 is a target in several preclinical and clinical trials for cancer treatment [156,157]. Concurrently, there is evidence that galectin 3 is a promising target for IPF [158] because it has a profibrotic action [159] that is partly mediated by binding to Muc1 [160].…”

Comparison of survivor scores for differentiation therapy of cancer to those for checkpoint inhibition: Half full or half empty

“…Potential new targets for therapy are directed toward inhibition of interleukin (IL)-3R activation in a subset of patients with mutant FLT3, 34,35 blocking STAT3 (epidermal growth factor receptor (EGFR) and IL-6) signaling pathways 36 and targeting MUC-1 to induce differentiation and increase survival. 37 It remains to be seen whether a subset of AML patients may benefit as much as other myeloid leukemia patients. It is quite likely that, as in the case of AML, identification of maturation arrest mutations or translocations in other cancers will be identified and appropriate blocking agents and effective treatments developed, for example, blocking pathways known to maintain stemness, such as Wnt, Oct-4, Notch, BMP, JAK, and others.…”

BIRC5 (baculoviral IAP repeat containing 5)

“…Other molecular signaling that has been involved in acute myeloid leukemia resistance is the expression of MUC1 (MUC1-C), an oncoprotein critical for the onset of tumorigenesis, which is overexpressed in acute myeloid leukemia blasts and leukemia stem cells. It has been demonstrated that targeting MUC1-C reduced BIRC5 levels and increased sensitivity to cytarabine, indicating that BIRC5 is involved in multiple signaling pathways required for survival in leukemia cells (Stroopinsky et al, 2018). Acute lymphoblastic leukemia (ALL) patients also presented elevated levels of BIRC5 and VEGF, especially prior to treatment with an association of idarubicin, cytosine arabinoside and etoposide.…”