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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4429-4436.
Prepublished online as a Blood First Edition Paper on January 18, 2005; DOI 10.1182/blood-2004-08-3096.
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Submitted August 10, 2004
Accepted December 29, 2004
A neurotrophin axis in myeloma: TrkB and BDNF promote tumor cell survival
Roger N Pearse*, Steven L Swendeman, Ying Li, Dahlia Rafii, and Barbara L Hempstead
Division of Hematology, Cornell University Medical College, New York, NY, USA
* Corresponding author; email: rnp2001{at}med.cornell.edu.
Multiple myeloma (MM) is a B-cell neoplasm which is characterized by the clonal expansion of malignant plasma cells, and is frequently associated with chromosomal translocations placing an oncogene under the control of the immunoglobulin heavy chain enhancer. Despite these pathogenic translocations, MM cells remain dependent upon external cues for survival. We present evidence that BDNF, a member of the neurotrophin family of growth factors, and its high affinity receptor, TrkB, contribute to these survival cues. MM cells express TrkB, and respond to BDNF by activating MAPK and PI3K/Akt signaling cascades. Addition of BDNF protects human MM cell lines (HMCL) from apoptosis induced by dexamethasone or bortezomib, and prolongs the survival of primary MM cells cultured alone or with human BM stroma. As BDNF and TrkB are expressed by osteoblasts, stromal cells and endothelial cells within the BM microenvironment, a BDNF:TrkB axis may be critical to the interactions of MM with bone and stroma that contribute to MM tumor progression. Finally, BDNF is expressed by malignant plasma cells isolated from a subset of MM patients, as well as by most HMCL, suggesting a potential role for this neurotrophin axis in autocrine as well as paracrine support of MM.
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