Research Papers:

Notch signaling drives multiple myeloma induced osteoclastogenesis

Michela Colombo, Katja Thümmler, Leonardo Mirandola, Silvia Garavelli, Katia Todoerti, Luana Apicella, Elisa Lazzari, Marialuigia Lancellotti, Natalia Platonova, Moeed Akbar, Maurizio Chiriva-Internati, Richard Soutar, Antonino Neri, Carl S. Goodyear and Raffaella Chiaramonte _

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Oncotarget. 2014; 5:10393-10406. https://doi.org/10.18632/oncotarget.2084

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Michela Colombo1, Katja Thümmler2, Leonardo Mirandola1, Silvia Garavelli1, Katia Todoerti6, Luana Apicella1, Elisa Lazzari1, Marialuigia Lancellotti1, Natalia Platonova1, Moeed Akbar2, Maurizio Chiriva-Internati4, Richard Soutar5, Antonino Neri3, Carl S. Goodyear2 and Raffaella Chiaramonte1

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

2 Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

3 Department of Clinical Sciences and Community Health, Università degli Studi di Milano; Hematology, Fondazione Cà Granda IRCCS Policlinico, Milano, Italy

4 Division of Hematology and Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, TX, USA

5 Beatson West of Scotland Cancer Centre, Haemato-oncology Service, Gartnavel Hospital, Glasgow, UK

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


Raffaella Chiaramonte, email:

Antonino Neri, email:

Keywords: Myeloma, Notch, Jagged, RANKL, bone disease

Received: May 17, 2014 Accepted: June 7, 2014 Published: June 9, 2014


Multiple myeloma (MM) is closely associated with bone destruction. Once migrated to the bone marrow, MM cells unbalance bone formation and resorption via the recruitment and maturation of osteoclast precursors.

The Notch pathway plays a key role in different types of cancer and drives several biological processes relevant in MM, including cell localization within the bone marrow, proliferation, survival and pharmacological resistance.

Here we present evidences that MM can efficiently drive osteoclastogenesis by contemporaneously activating Notch signaling on tumor cells and osteoclasts through the aberrant expression of Notch ligands belonging to the Jagged family. Active Notch signaling in MM cells induces the secretion of the key osteoclastogenic factor, RANKL, which can be boosted in the presence of stromal cells. In turn, MM cells-derived RANKL causes the upregulation of its receptor, RANK, and Notch2 in pre-osteoclasts. Notch2 stimulates osteoclast differentiation by promoting autocrine RANKL signaling. Finally, MM cells through Jagged ligands expression can also activate Notch signaling in pre-osteoclast by direct contact.

Such synergism between tumor cells and pre-osteoclasts in MM-induced osteoclastogenesis can be disrupted by silencing tumor-derived Jagged1 and 2. These results make the Jagged ligands new promising therapeutic targets in MM to contrast bone disease and the associated co-morbidities.

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