Role of human Bone Marrow-Mesenchymal Stromal Cells-mediated Notch signaling on acute myeloid leukemia cells survival and proliferation in vitro

Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. However, its role in human Acute Myelogenous Leukemia (AML) remains unclear. In the present study, we investigated the role of Notch pathway in the development, progression and relapse of human AML. The expression of Notch receptors (Notch1, Notch2, Notch3 and Notch4) and their ligands (DLL1, DLL3, DLL4, Jagged1 and Jagged2) have been analyzed in human AML cell lines HL-60, THP1, U937, K562 and primary AML samples by flow cytometry, western immunoblotting and RT-PCR approaches. In addition, the phenotype of Notch receptors has been evaluated in the same cell populations cocultured both with human MSCs from healthy donors (hBM-MSCs) and from AML patients (hBM-AML-MSCs). Furthermore, we analyzed AML cell survival and proliferation upon treatment with Notch inhibitor GSI-XII and chemotherapeutic drugs. We observed that human AML samples expressed Notch receptors and ligands at activated levels and also downstream Notch targets, suggesting that Notch pathway is functional at basal levels in human AML. In addition, MSCs protect AML cells from apoptosis even in the presence of chemotherapeutic drugs. This study shows new possible interactions between the bone marrow stromal microenvironment and leukemia cells