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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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Submitted May 31, 2007
Accepted August 10, 2007
MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts
Sonia Vallet, Noopur Raje, Kenji Ishitsuka, Teru Hideshima, Klaus Podar, Shweta Chhetri, Samantha Pozzi, Iris Breitkreutz, Tanyel Kiziltepe, Hiroshi Yasui, Enrique M. Ocio, Norihiko Shiraishi, Janice Jin, Yutaka Okawa, Hiroshi Ikeda, Siddhartha Mukherjee, Nileshwari Vaghela, Diana Cirstea, Marco Ladetto, Mario Boccadoro, and Kenneth C Anderson*
Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, United States
Cattedra di Ematologia, Dipartimento di Medicina ed Oncologia Sperimentale, Universita di Torino, Torino, Italy
* Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu.
The interaction between osteoclasts (OC) 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, OC 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 downregulation of c-fos signaling. OC 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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