title: The amyloidogenic light chain is a stressor that sensitizes plasma cells to proteasome inhibitor toxicity.
abstract: Systemic light chain (AL) amyloidosis is caused by the clonal production of an unstable immunoglobulin light chain (LC), which affects organ function systemically. Although pathogenic LCs have been characterized biochemically, little is known about the biology of amyloidogenic plasma cells (PCs). Intrigued by the unique response rates of AL amyloidosis patients to the first-in-class proteasome inhibitor (PI) bortezomib, we purified and investigated patient-derived AL PCs, in comparison with primary multiple myeloma (MM) PCs, the prototypical PI-responsive cells. Functional, biochemical, and morphological characterization revealed an unprecedented intrinsic sensitivity of AL PCs to PIs, even higher than that of MM PCs, associated with distinctive organellar features and expression patterns indicative of cellular stress. These consisted of expanded endoplasmic reticulum (ER), perinuclear mitochondria, and a higher abundance of stress-related transcripts, and were consistent with reduced autophagic control of organelle homeostasis. To test whether PI sensitivity stems from AL LC production, we engineered PC lines that can be induced to express amyloidogenic and nonamyloidogenic LCs, and found that AL LC expression alters cell growth and proteostasis and confers PI sensitivity. Our study discloses amyloidogenic LC production as an intrinsic PC stressor, and identifies stress-responsive pathways as novel potential therapeutic targets. Moreover, we contribute a cellular disease model to dissect the biology of AL PCs.
authors.affiliation: Unit of Age Related Diseases, Division of Genetics and Cell Biology.
authors.forename: Laura
authors.initials: L
authors.lastname: Oliva
authors.affiliation: Unit of Age Related Diseases, Division of Genetics and Cell Biology.
authors.forename: Ugo
authors.initials: U
authors.lastname: Orfanelli
authors.affiliation: Unit of Age Related Diseases, Division of Genetics and Cell Biology.
authors.forename: Massimo
authors.initials: M
authors.lastname: Resnati
authors.affiliation: Imaging Research Center, and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Raimondi
authors.affiliation: Unit of Protein Transport and Secretion, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Orsi
authors.affiliation: Unit of Age Related Diseases, Division of Genetics and Cell Biology.
authors.forename: Enrico
authors.initials: E
authors.lastname: Milan
authors.affiliation: Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.|Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Palladini
authors.affiliation: Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.|Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Milani
authors.affiliation: Department of Veterinary Sciences, University of Turin, Turin, Italy.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Cerruti
authors.affiliation: Department of Veterinary Sciences, University of Turin, Turin, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cascio
authors.affiliation: Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.|Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Casarini
authors.affiliation: Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.|Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rognoni
authors.affiliation: Unit of Biology of Myelin, Division of Genetics and Cell Biology, and.
authors.forename: Thierry
authors.initials: T
authors.lastname: Touvier
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Department of Oncohematology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Magda
authors.initials: M
authors.lastname: Marcatti
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Department of Oncohematology, San Raffaele Scientific Institute, Milan, Italy.|Università Vita-Salute San Raffaele, Milan, Italy; and.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.affiliation: Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Mangiacavalli
authors.affiliation: Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corso
authors.affiliation: Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.|Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.affiliation: Unit of Age Related Diseases, Division of Genetics and Cell Biology.|Università Vita-Salute San Raffaele, Milan, Italy; and.
authors.forename: Simone
authors.identifier: 0000-0003-1215-7518
authors.initials: S
authors.lastname: Cenci
mesh_terms: D000686:Amyloidosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000069286:Bortezomib / Q000493:pharmacokinetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis*; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010950:Plasma Cells / Q000378:metabolism* / Q000473:pathology; D061988:Proteasome Inhibitors / Q000493:pharmacokinetics*
chemical_list: D007147:Immunoglobulin Light Chains; D061988:Proteasome Inhibitors; D000069286:Bortezomib