Notch signaling deregulation in multiple myeloma: A rational molecular target

Michela Colombo, Serena Galletti, Silvia Garavelli, Natalia Platonova, Alessandro Paoli, Andrea Basile, Elisa Taiana, Antonino Neri, Raffaella Chiaramonte

Research output: Contribution to journalArticle

Abstract

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 nontumor 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 Notchrelated 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.

Original languageEnglish
Pages (from-to)26826-26840
Number of pages15
JournalOncotarget
Volume6
Issue number29
DOIs
Publication statusPublished - 2015

Keywords

  • Molecular
  • Multiple myeloma
  • Notch
  • Therapy

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Colombo, M., Galletti, S., Garavelli, S., Platonova, N., Paoli, A., Basile, A., Taiana, E., Neri, A., & Chiaramonte, R. (2015). Notch signaling deregulation in multiple myeloma: A rational molecular target. Oncotarget, 6(29), 26826-26840. https://doi.org/10.18632/oncotarget.5025