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Blood, 15 January 2008, Vol. 111, No. 2, pp. 549-557.
Prepublished online as a Blood First Edition Paper on November 2, 2007; DOI 10.1182/blood-2007-05-090852.
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Submitted May 17, 2007
Accepted September 25, 2007
Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-)amyloidosis is associated with response to high-dose melphalan
Ping Zhou, Julie Teruya-Feldstein, Ping Lu, Martin Fleisher, Adam Olshen, and Raymond L. Comenzo*
Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
Department of Clinical Laboratories, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
Hematology Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
* Corresponding author; email: comenzor{at}mskcc.org.
In high doses with stem cell transplant, melphalan is an effective but toxic therapy for patients with systemic light-chain (AL-)amyloidosis, a protein deposition and monoclonal plasma cell disease. Melphalan can eliminate the indolent clonal plasma cells that cause the disease, an achievement called a complete response. Such a response is usually associated with extended survival while no response (a less than 50% reduction) is not. Gene-expression studies and a stringent supervised analysis identified calreticulin as having significantly higher expression in the pre-treatment plasma cells of patients with systemic AL-amyloidosis who then had a complete response to high-dose melphalan. Calreticulin is a pleiotropic calcium-binding protein found in the endoplasmic reticulum and the nucleus whose over-expression is associated with increased sensitivity to apoptotic stimuli. Real-time PCR and immunohistochemical staining also showed that expression of calreticulin was higher in the plasma cells of those with a complete response. Furthermore, wild type murine embryonic fibroblasts were significantly more sensitive to melphalan than calreticulin knock-out murine embryonic fibroblasts. These data have important implications for understanding the activity of melphalan in plasma cell diseases and support further investigation of calreticulin and its modulation in patients with systemic AL-amyloidosis receiving high-dose melphalan. This study was registered at www.ClinicalTrials.gov as #NCT00089167.
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