The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma

Vdovin, Alexander; Jelı́nek, Tomáš; Žihala, David; Ševčíková, Tereza; Ďurech, Michal; Sahinbegovic, Hana; Snaurova, Renata; Radhakrishnan, Dhwani; Turi, Marcello; Chyra, Zuzana; Popková, Tereza; Venglár, Ondrej; Hrdinka, Matouš; Hájek, Roman; Šimíček, Michal

doi:10.1038/s41467-022-34654-2

Cited by 12 publications

(6 citation statements)

References 58 publications

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“…In addition, apoptosis induced upon proteasome inhibition was correlated with the amount of Ig production (Meister et al, 2007). Consistent with a major role for Ig production in myeloma cell survival, a positive correlation between the amount of intracellular Ig light chains (LC) in tumor PCs and progression free survival (PFS) has been recently observed in newly diagnosed MM patients (Vdovin et al, 2022).…”

Section: Introductionmentioning

confidence: 72%

Disruption of immunoglobulin heavy and light chain assembly by antisense oligonucleotides impairs protein homeostasis and myeloma cell survival

Horiot,

Roussel,

Praité

et al. 2023

Preprint

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Multiple myeloma (MM) is related to the accumulation of malignant plasma cells (PCs) in the bone marrow. MM accounts for approximatively 10% of hematological malignancies and despite major improvement in therapies and outcomes, relapses will virtually occur in all patients. Usually, the disease goes along with an excess production of a monoclonal immunoglobulin (Ig) component by the tumor PC clone. However, many questions remain regarding the consequences of a deregulated Ig production on PC survival. Recent advances in RNA-based therapy using antisense oligonucleotides (ASO) prompted us to examine the impact of altered Ig heavy to light chain (HC/LC) ratios in MM cells. We designed a pan IgG subclasses specific ASO targeting a consensus sequence found in the polyadenylation signal (PAS) of all secreted IGHG mRNAs (IgG-ASO). Remarkably, treatment with this compound strongly decreased IgG secretion in MM cell lines and patient cells. Consistent with a deregulated HC/LC ratio, a dose-dependent excess of free-LCs (as monomers and dimers) was observed in myeloma cells treated with IgG-ASO, compared to an irrevelant control ASO (CTRL). RNA-seq profiles further indicated that the expression of genes involved in cellular metabolism, unfolded protein response (UPR) and cell death pathways were altered after treatment with IgG-ASO. Interestingly, impaired survival of primary IgG-expressing cells isolated from MM patients was achieved upon treatment with IgG-ASO, whereas no major effect was observed for healthy cells. Altogether, our data provide evidence for efficient inhibition of IgG secretion upon ASO treatment and suggest that an excess of free-LC due to disruption of HC/LC stoichiometry is toxic for MM cells expressing complete Ig. Such RNA-based strategies targeting PC in an Ig isotype-dependent manner could open new avenues for selective therapeutic approaches in PC dyscrasias.

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Section: Introductionmentioning

confidence: 72%

Disruption of immunoglobulin heavy and light chain assembly by antisense oligonucleotides impairs protein homeostasis and myeloma cell survival

Horiot,

Roussel,

Praité

et al. 2023

Preprint

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“…DUBs play an important role in hematological malignancies ( 24 ). MM cells express different DUBs, and these are suggested as potential treatment targets and are currently exploited in clinical trials (VLX1570, USP14 inhibitor, NCT02372240) ( 29 , 30 ). Results from our screen of a broader panel of DUB inhibitors indicate that several of the USP-DUBs are involved in the deubiquitination of IL-32 in MM cells.…”

Section: Discussionmentioning

confidence: 99%

The pro-tumorigenic cytokine IL-32 has a high turnover in multiple myeloma cells due to proteolysis regulated by oxygen-sensing cysteine dioxygenase and deubiquitinating enzymes

Kastnes,

Aass,

Bouma

et al. 2023

Front. Oncol.

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IL-32 is a pro-inflammatory cytokine expressed by several types of cancer cells and immune cells. Currently, no treatment targeting IL-32 is available, and its intracellular and exosomal localization make IL-32 less accessible to drugs. We previously showed that hypoxia promotes IL-32 expression through HIF1α in multiple myeloma cells. Here, we demonstrate that high-speed translation and ubiquitin-dependent proteasomal degradation lead to a rapid IL-32 protein turnover. We find that IL-32 protein half-life is regulated by the oxygen-sensing cysteine-dioxygenase ADO and that deubiquitinases actively remove ubiquitin from IL-32 and promote protein stability. Deubiquitinase inhibitors promoted the degradation of IL-32 and may represent a strategy for reducing IL-32 levels in multiple myeloma. The fast turnover and enzymatic deubiquitination of IL-32 are conserved in primary human T cells; thus, deubiquitinase inhibitors may also affect T-cell responses in various diseases.

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“…M-protein, which is considered as a diagnostic hallmark of the all monoclonal gammopathies is one of the main values measured for every MM patient ( Chim et al, 2018 ). Recent research proved that intracellular Ig (iIg) concentration represents the myeloma Ig production capacity more precisely than M-protein, that’s why quantification of iIg from aberrant plasma cells could serve as a better estimate of the immunoglobulins synthesis rate ( Yan et al, 2020 ) Indeed, iIg is a robust, independent factor that can be used to predict the course of the disease in patients treated with the PI-based therapy ( Vdovin et al, 202 2).…”

Section: Sensitivity To Proteasome Inhibitorsmentioning

confidence: 99%

Factors determining the sensitivity to proteasome inhibitors of multiple myeloma cells

Pelon,

Krzeminski,

Tracz-Gaszewska

et al. 2024

Front. Pharmacol.

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Multiple myeloma is an incurable cancer that originates from antibody-producing plasma cells. It is characterized by an intrinsic ability to produce large amounts of immunoglobulin-like proteins. The high rate of synthesis makes myeloma cells dependent on protein processing mechanisms related to the proteasome. This dependence made proteasome inhibitors such as bortezomib and carfilzomib one of the most important classes of drugs used in multiple myeloma treatment. Inhibition of the proteasome is associated with alteration of a number of important biological processes leading, in consequence, to inhibition of angiogenesis. The effect of drugs in this group and the degree of patient response to the treatment used is itself an extremely complex process that depends on many factors. At cellular level the change in sensitivity to proteasome inhibitors may be related to differences in the expression level of proteasome subunits, the degree of proteasome loading, metabolic adaptation, transcriptional or epigenetic factors. These are just some of the possibilities that may influence differences in response to proteasome inhibitors. This review describes the main cellular factors that determine the degree of response to proteasome inhibitor drugs, as well as information on the key role of the proteasome and the performance characteristics of the inhibitors that are the mainstay of multiple myeloma treatment.

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The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma

Cited by 12 publications

References 58 publications

Disruption of immunoglobulin heavy and light chain assembly by antisense oligonucleotides impairs protein homeostasis and myeloma cell survival

Disruption of immunoglobulin heavy and light chain assembly by antisense oligonucleotides impairs protein homeostasis and myeloma cell survival

The pro-tumorigenic cytokine IL-32 has a high turnover in multiple myeloma cells due to proteolysis regulated by oxygen-sensing cysteine dioxygenase and deubiquitinating enzymes

Factors determining the sensitivity to proteasome inhibitors of multiple myeloma cells

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