Oncotarget

Research Papers: Pathology:

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 and Raffaella Chiaramonte _

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Oncotarget. 2016; 7:56013-56029. https://doi.org/10.18632/oncotarget.10820

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Abstract

Michela Colombo1,*, Serena Galletti2,*, Gaetano Bulfamante1,3, Monica Falleni1,3, Delfina Tosi1,3, Katia Todoerti4, Elisa Lazzari1,5,6, Leslie A. Crews5,6, Catriona H.M. Jamieson5,6, Sara Ravaioli1, Francesco Baccianti1, Silvia Garavelli1, Natalia Platonova2, Antonino Neri2 and Raffaella Chiaramonte1

1 Department of Health Sciences, Università degli Studi di Milano, Milano, Italy

2 Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Hematology Unit, Fondazione Cà Granda IRCCS Policlinico, Milano, Italy

3 Unit of Pathology A.O. San Paolo, Milan, Italy

4 Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy

5 Department of Medicine, Division of Regenerative Medicine, Moores Cancer Center at University of California, San Diego, La Jolla, CA, USA

6 Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA

* These authors have contributed equally to this manuscript

Correspondence to:

Antonino Neri, email:

Raffaella Chiaramonte, email:

Keywords: multiple myeloma, Notch signaling, Jagged, interleukin-6, bone marrow niche, Pathology Section

Received: January 18, 2016 Accepted: July 06, 2016 Published: July 24, 2016

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.


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