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 Blood, 15 November 2007, Vol. 110, No. 10, pp. 3744-3752.
Prepublished online as a Blood First Edition Paper on August 22, 2007; DOI 10.1182/blood-2007-05-093294.

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NEOPLASIA

MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts

Sonia Vallet1,2, Noopur Raje1,3, Kenji Ishitsuka1, Teru Hideshima1, Klaus Podar1, Shweta Chhetri1, Samantha Pozzi1, Iris Breitkreutz1, Tanyel Kiziltepe1, Hiroshi Yasui1, Enrique M. Ocio1, Norihiko Shiraishi1, Janice Jin1, Yutaka Okawa1, Hiroshi Ikeda1, Siddhartha Mukherjee3, Nileshwari Vaghela1, Diana Cirstea1, Marco Ladetto2, Mario Boccadoro2, and Kenneth C. Anderson1

1 Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 2 Division of Hematology, University of Turin, Turin, Italy; and 3 Division of Hematology and Oncology, Massachusetts General Hospital, Boston

The interaction between osteoclasts (OCs) and multiple myeloma (MM) cells plays a key role in the pathogenesis of MM-related osteolytic bone disease (OBD). MM cells promote OC formation and, in turn, OCs enhance MM cell proliferation. Chemokines are mediators of MM effects on bone and vice versa; in particular, CCL3 enhances OC formation and promotes MM cell migration and survival. Here, we characterize the effects of MLN3897, a novel specific antagonist of the chemokine receptor CCR1, on both OC formation and OC-MM cell interactions. MLN3897 demonstrates significant impairment of OC formation (by 40%) and function (by 70%), associated with decreased precursor cell multinucleation and down-regulation of c-fos signaling. OCs secrete high levels of CCL3, which triggers MM cell migration; conversely, MLN3897 abrogates its effects by inhibiting Akt signaling. Moreover, MM cell-to-OC adhesion was abrogated by MLN3897, thereby inhibiting MM cell survival and proliferation. Our results therefore show novel biologic sequelae of CCL3 and its inhibition in both osteoclastogenesis and MM cell growth, providing the preclinical rationale for clinical trials of MLN3897 to treat OBD in MM.


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