Notch signaling deregulation in multiple myeloma: A rational molecular target
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Michela Colombo1,*, Serena Galletti2,*, Silvia Garavelli1, Natalia Platonova2, Alessandro Paoli1, Andrea Basile1, Elisa Taiana2, Antonino Neri2, Raffaella Chiaramonte1
1Department of Health Sciences, Università degli Studi di Milano, 20142 Milano, Italy
2Department of Clinical Sciences and Community Health, Università degli Studi di Milano; Hematology, Fondazione Cà Granda IRCCS Policlinico, 20122 Milano, Italy
*These authors have contributed equally to this work
Antonino Neri, e-mail: [email protected]
Raffaella Chiaramonte, e-mail: [email protected]
Keywords: Notch, multiple myeloma, molecular, therapy
Received: May 19, 2015 Accepted: August 03, 2015 Published: August 13, 2015
Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches.
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