MSLN expression predicts a high risk of EMD in AML by promoting cell adhesion and metastasis via interaction with MUC16

The overall incidence of extramedullary disease (EMD) in acute myeloid leukemia (AML) ranges from 2% to 30.5%, and is potentially associated with short overall survival. However, the risk factors for EMD and the underlying molecular mechanisms remain poorly understood. Here, we analyzed a cohort of 118 adult patients with de novo AML, among whom 27 (22.88%) developed EMD in various body sites, with tissue involvement as the most common (13.56%, 16/118). Mesothelin (MSLN) expression, detectable at both transcript and protein levels, can serve as an independent risk factor for EMD in patients with AML. Multivariate analyses revealed that MSLN-positivity at transcript levels (HR, 3.43; 95% CI, 1.44 to 8.20; P =0.006) and MSLN-positivity on leukemic blasts detected by flow cytometry (HR, 3.28; 95% CI, 1.37 to 7.86; P =0.008) are independently correlated with EMD risk. Mechanistically, MSLN overexpression promotes cell proliferation, metastasis, and invasion in AML cells. MSLN greatly facilitates cell-cell adhesion by binding with MUC16, resulting in extramedullary dissemination. MSLN also activates the PI3K signaling pathway and upregulates neural cell adhesion molecules (CAMs) CD56 and NCAM2 through interaction with MUC16. Our study highlights the importance of MSLN expression, particularly identified by flow cytometry, as an independent risk factor for EMD in patients with AML, and elucidates its role in modulating PI3K signaling and CAMs in AML cells.