Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan.
In high doses with stem-cell transplantation, 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 stringently supervised analysis identified calreticulin as having significantly higher expression in the pretreatment 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 overexpression 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.
Zhou
Ping
P
Sloan-Kettering Institute, Department of Pathology, New York, NY 10021, USA.
Teruya-Feldstein
Julie
J
Lu
Ping
P
Fleisher
Martin
M
Olshen
Adam
A
Comenzo
Raymond L
RL
D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D037282:Calreticulin / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007147:Immunoglobulin Light Chains; D007150:Immunohistochemistry; D008297:Male; D008558:Melphalan / Q000008:administration & dosage* / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D019653:Myeloablative Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D010950:Plasma Cells / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous
D037282:Calreticulin; D007147:Immunoglobulin Light Chains; D019653:Myeloablative Agonists; D008558:Melphalan