The amyloidogenic light chain is a stressor that sensitizes plasma cells to proteasome inhibitor toxicity

• Published in: Blood 2017-04, Vol.129 (15), p.2132-2142
• Main Authors: Oliva, Laura, Orfanelli, Ugo, Resnati, Massimo, Raimondi, Andrea, Orsi, Andrea, Milan, Enrico, Palladini, Giovanni, Milani, Paolo, Cerruti, Fulvia, Cascio, Paolo, Casarini, Simona, Rognoni, Paola, Touvier, Thierry, Marcatti, Magda, Ciceri, Fabio, Mangiacavalli, Silvia, Corso, Alessandro, Merlini, Giampaolo, Cenci, Simone
• Format: Article
• Language: English
• Subjects: Amyloidosis - drug therapy; Amyloidosis - metabolism; Amyloidosis - pathology; Bortezomib - pharmacokinetics; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Female; Humans; Immunoglobulin Light Chains - biosynthesis; Male; Mitochondria - metabolism; Mitochondria - pathology; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Plasma Cells - metabolism; Plasma Cells - pathology; Proteasome Inhibitors - pharmacokinetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-08-730978

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. •Amyloidogenic PCs show unique PI susceptibility and altered organelle homeostasis, consistent with defective autophagy.•Amyloidogenic LC production is an intrinsic cellular stressor that sensitizes to PI toxicity.