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

Laura Oliva, U Orfanelli, M Resnati, A Raimondi, A Orsi, E Milan, G Palladini, P Milani, F Cerruti, Paolo Cascio, S Casarini, P Rognoni, T Touvier, M Marcatti, F Ciceri, S Mangiacavalli, A Corso, G Merlini, S Cenci

Research output: Contribution to journalArticle

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 ALPCs 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, anda 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,wecontribute a cellular disease model to dissect the biology of ALPCs. © 2017 by The American Society of Hematology.
Original languageEnglish
Pages (from-to)2132-2142
Number of pages11
JournalBlood
Volume129
Issue number15
DOIs
Publication statusPublished - 2017

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Proteasome Inhibitors
Plasma Cells
Toxicity
Plasmas
Light
Amyloidosis
Multiple Myeloma
Immunoglobulin Light Chains
Mitochondria
Cell growth
Endoplasmic Reticulum
Organelles
Homeostasis
Cells
Cell Line
Growth

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The amyloidogenic light chain is a stressor that sensitizes plasma cells to proteasome inhibitor toxicity. / Oliva, Laura; Orfanelli, U; Resnati, M; Raimondi, A; Orsi, A; Milan, E; Palladini, G; Milani, P; Cerruti, F; Cascio, Paolo; Casarini, S; Rognoni, P; Touvier, T; Marcatti, M; Ciceri, F; Mangiacavalli, S; Corso, A; Merlini, G; Cenci, S.

In: Blood, Vol. 129, No. 15, 2017, p. 2132-2142.

Research output: Contribution to journalArticle

Oliva, Laura ; Orfanelli, U ; Resnati, M ; Raimondi, A ; Orsi, A ; Milan, E ; Palladini, G ; Milani, P ; Cerruti, F ; Cascio, Paolo ; Casarini, S ; Rognoni, P ; Touvier, T ; Marcatti, M ; Ciceri, F ; Mangiacavalli, S ; Corso, A ; Merlini, G ; Cenci, S. / The amyloidogenic light chain is a stressor that sensitizes plasma cells to proteasome inhibitor toxicity. In: Blood. 2017 ; Vol. 129, No. 15. pp. 2132-2142.
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AU - Oliva, Laura

AU - Orfanelli, U

AU - Resnati, M

AU - Raimondi, A

AU - Orsi, A

AU - Milan, E

AU - Palladini, G

AU - Milani, P

AU - Cerruti, F

AU - Cascio, Paolo

AU - Casarini, S

AU - Rognoni, P

AU - Touvier, T

AU - Marcatti, M

AU - Ciceri, F

AU - Mangiacavalli, S

AU - Corso, A

AU - Merlini, G

AU - Cenci, S

PY - 2017

Y1 - 2017

N2 - 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 ALPCs 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, anda 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,wecontribute a cellular disease model to dissect the biology of ALPCs. © 2017 by The American Society of Hematology.

AB - 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 ALPCs 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, anda 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,wecontribute a cellular disease model to dissect the biology of ALPCs. © 2017 by The American Society of Hematology.

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