Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan

Blood. 2008 Jan 15;111(2):549-57. doi: 10.1182/blood-2007-05-090852. Epub 2007 Nov 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloidosis / genetics
  • Amyloidosis / metabolism*
  • Amyloidosis / mortality
  • Amyloidosis / pathology
  • Amyloidosis / therapy
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Calreticulin / biosynthesis
  • Calreticulin / genetics
  • Cell Line
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / pathology
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / pathology
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Humans
  • Immunoglobulin Light Chains*
  • Immunohistochemistry
  • Male
  • Melphalan / administration & dosage*
  • Melphalan / adverse effects
  • Mice
  • Mice, Knockout
  • Myeloablative Agonists / administration & dosage*
  • Myeloablative Agonists / adverse effects
  • Plasma Cells / metabolism*
  • Plasma Cells / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cell Transplantation
  • Transplantation, Autologous


  • Calreticulin
  • Immunoglobulin Light Chains
  • Myeloablative Agonists
  • Melphalan