Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche

Michela Colombo, Serena Galletti, Gaetano Bulfamante, Monica Falleni, Delfina Tosi, Katia Todoerti, Elisa Lazzari, Leslie A. Crews, Catriona H M Jamieson, Sara Ravaioli, Francesco Baccianti, Silvia Garavelli, Natalia Platonova, Antonino Neri, Raffaella Chiaramonte

Research output: Contribution to journalArticlepeer-review

Abstract

Multiple myeloma cell growth relies on intrinsic aggressiveness, due to a high karyotypic instability, or on the support from bone marrow (BM) niche. We and other groups have provided evidences that Notch signaling is related to tumor cell growth, pharmacological resistance, localization/recirculation in the BM and bone disease. This study indicates that high gene expression levels of Notch signaling members (JAG1, NOTCH2, HES5 and HES6) correlate with malignant progression or high-risk disease, and Notch signaling may participate in myeloma progression by increasing the BM levels of interleukin-6 (IL-6), a major player in myeloma cell growth and survival. Indeed, in vitro results, confirmed by correlation analysis on gene expression profiles of myeloma patients and immunohistochemical studies, demonstrated that Notch signaling controls IL-6 gene expression in those myeloma cells capable of IL-6 autonomous production as well as in surrounding BM stromal cells. In both cases Notch signaling activation may be triggered by myeloma cell-derived Jagged ligands. The evidence that Notch signaling positively controls IL-6 in the myeloma-associated BM makes this pathway a key mediator of tumor-directed reprogramming of the bone niche. This work strengthens the rationale for a novel Notch-directed therapy in multiple myeloma based on the inhibition of Jagged ligands.

Original languageEnglish
Pages (from-to)56013-56029
Number of pages17
JournalOncotarget
Volume7
Issue number35
DOIs
Publication statusPublished - 2016

Keywords

  • Bone marrow niche
  • Interleukin-6
  • Jagged
  • Multiple myeloma
  • Notch signaling
  • Pathology Section

ASJC Scopus subject areas

  • Oncology

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