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

Laura Oliva, Ugo Orfanelli, Massimo Resnati, Andrea Raimondi, Andrea Orsi, Enrico Milan, Giovanni Palladini, Paolo Milani, Fulvia Cerruti, Paolo Cascio, Simona Casarini, Paola Rognoni, Thierry Touvier, Magda Marcatti, Fabio Ciceri, Silvia Mangiacavalli, Alessandro Corso, Giampaolo Merlini, Simone Cenci

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2132-2142
Number of pages11
JournalBlood
Volume129
Issue number15
DOIs
Publication statusPublished - Apr 13 2017

Fingerprint

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

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

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

In: Blood, Vol. 129, No. 15, 13.04.2017, p. 2132-2142.

Research output: Contribution to journalArticle

@article{9084607864d94dc1b15da32fec0d58e0,
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 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.",
author = "Laura Oliva and Ugo Orfanelli and Massimo Resnati and Andrea Raimondi and Andrea Orsi and Enrico Milan and Giovanni Palladini and Paolo Milani and Fulvia Cerruti and Paolo Cascio and Simona Casarini and Paola Rognoni and Thierry Touvier and Magda Marcatti and Fabio Ciceri and Silvia Mangiacavalli and Alessandro Corso and Giampaolo Merlini and Simone Cenci",
year = "2017",
month = "4",
day = "13",
doi = "10.1182/blood-2016-08-730978",
language = "English",
volume = "129",
pages = "2132--2142",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "15",

}

TY - JOUR

T1 - The amyloidogenic light chain is a stressor that sensitizes plasma cells to proteasome inhibitor toxicity

AU - Oliva, Laura

AU - Orfanelli, Ugo

AU - Resnati, Massimo

AU - Raimondi, Andrea

AU - Orsi, Andrea

AU - Milan, Enrico

AU - Palladini, Giovanni

AU - Milani, Paolo

AU - Cerruti, Fulvia

AU - Cascio, Paolo

AU - Casarini, Simona

AU - Rognoni, Paola

AU - Touvier, Thierry

AU - Marcatti, Magda

AU - Ciceri, Fabio

AU - Mangiacavalli, Silvia

AU - Corso, Alessandro

AU - Merlini, Giampaolo

AU - Cenci, Simone

PY - 2017/4/13

Y1 - 2017/4/13

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85019225158&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019225158&partnerID=8YFLogxK

U2 - 10.1182/blood-2016-08-730978

DO - 10.1182/blood-2016-08-730978

M3 - Article

C2 - 28130214

AN - SCOPUS:85019225158

VL - 129

SP - 2132

EP - 2142

JO - Blood

JF - Blood

SN - 0006-4971

IS - 15

ER -