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Molecular targets for therapy

Redirecting proteoxicity

Leukemia volume 34, pages 3109–3110 (2020)Cite this article

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The Original Article was published on 09 April 2020

In a recent issue of Leukemia, Cohen and Wechalekar review recent advancements in the diagnosis and therapy of systemic amyloidoses, which are bringing these conditions from the darkness to the spotlight [1]. In their excellent review, the authors underline that the therapeutic strategy is centered on the profound reduction of misfolded proteins or on their stabilization in order to halt the amyloid cascade and the noxious proteotoxic and infiltrative effects on target tissues. In particular, the authors highlight the role of bortezomib as an established mainstay of upfront treatment for the majority of patients with AL amyloidosis due to its capability of rapidly inducing a profound reduction of the amyloidogenic clone and circulating light chains [1]. In the largest series of AL patients reported so far, frontline bortezomib-based regimens led to an overall response rate of 65%, including deep hematologic responses in almost half of the cases [2].

Why is the amyloidogenic clone so sensitive to proteasome inhibition? Data obtained on primary AL plasma cells, derived from patients’ bone marrow, and in plasma cell line engineered to express amyloid light chains, showed increased intracellular oxidative stress and significantly higher sensitivity to proteasome inhibition compared to plasma cells producing non-misfolded myeloma light chains [3]. These data suggest that the ubiquitin-proteasome system (UPS) is vital for alleviating the proteotoxic burden of misfolded proteins in amyloid plasma cells, and hampering this pathway represents a targeted treatment.

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Fig. 1: Redirecting proteotoxicity against tumoral plasma cells.

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Acknowledgements

This work was supported by a grant from the Amyloidosis Foundation “Inhibiting deubiquitinases to treat AL amyloidosis”, “Associazione Italiana per la Ricerca sul Cancro–Special Program Molecular Clinical Oncology 5 per mille” (Grant 9965), Fondazione CARIPLO (Grant nos 2013-0964 and 2018-0257); Italian Ministry of Health target project (Grant nos RF-2013-02355259 and GR-2018-12368387), the Cancer Research UK, FCAECC and AIRC under the Accelerator Award 2017 Program.

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  1. Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy

    Mario Nuvolone & Giampaolo Merlini

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  1. Mario Nuvolone
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  2. Giampaolo Merlini
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Correspondence to Giampaolo Merlini.

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MN: speaker honoraria from Janssen-Cilag; GM, consultant: Millennium Pharmaceuticals, Inc., Pfizer, Janssen-Cilag, Prothena, and IONIS.

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Nuvolone, M., Merlini, G. Redirecting proteoxicity. Leukemia 34, 3109–3110 (2020). https://doi.org/10.1038/s41375-020-01028-w

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