Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma

Zavidij, Oksana; Haradhvala, Nicholas J.; Mouhieddine, Tarek H.; Sklavenitis-Pistofidis, Romanos; Cai, Shanshan; Reidy, Mairéad; Rahmat, Mahshid; Flaifel, Abdallah; Ferland, Benjamin; Su, Nang Kham; Agius, Michael P.; Park, Jihye; Manier, Salomon; Bustoros, Mark; Huynh, Daisy; Capelletti, Marzia; Berrios, Brianna; Liu, Chia-Jen; He, Meng Xiao; Braggio, Esteban; Fonseca, Rafaël; Maruvka, Yosef E.; Guerriero, Jennifer L.; Goldman, Melissa; Allen, Eliezer M. Van; McCarroll, Steven A.; Azzi, Jamil; Getz, Gad; Ghobrial, Irène M.

doi:10.1038/s43018-020-0053-3

Cited by 245 publications

(240 citation statements)

References 63 publications

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“…However, the risk of infection decreased with the response to therapy, which suggests some immune reconstitution accompanies a lower burden of myeloma. In addition to progressive impairment of humoral immunity, changes across many cell types of the bone marrow immune microenvironment, including Natural Killer (NK), Dendritic, and T-cells, have been observed from MGUS, to SMM, and MM [69]. These observations support the concept that there is progressive immunoparesis that accompanies disease progression from MGUS to MM.…”

Section: Immunodeficiency In Mgusmentioning

confidence: 71%

Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

Lomas

Mouhieddine

Tahri

et al. 2020

Cancers

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Monoclonal Gammopathy of Undetermined Significance (MGUS) is considered to be a benign precursor condition that may progress to a lymphoproliferative disease or multiple myeloma. Most patients do not progress to an overt condition, but nevertheless, MGUS is associated with a shortened life expectancy and, in a minority of cases, a number of co-morbid conditions that include an increased fracture risk, renal impairment, peripheral neuropathy, secondary immunodeficiency, and cardiovascular disease. This review aims to consolidate current evidence for the significance of these co-morbidities before considering how best to approach these symptoms and signs, which are often encountered in primary care or within a number of specialties in secondary care.

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Section: Immunodeficiency In Mgusmentioning

confidence: 71%

Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

Lomas

Mouhieddine

Tahri

et al. 2020

Cancers

Self Cite

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“…Using single-cell RNA sequencing of bone marrow cells from the precursor stages of monoclonal gammopathy of unknown significance and smoldering multiple myeloma (SMM), to full-blown MM alongside healthy donors, Zavidij and colleagues [7] confirmed previous concepts about immune changes during patient progression [8], and provided unprecedented resolution about the immune microenvironment in precursor and malignant stages of MM. Interestingly, the same group of authors reported recently that most genetic alterations present in MM patients have already occurred by the time of SMM diagnosis, some of which predict risk of progression [9].…”

Section: Highlighted By Bruno Paivamentioning

confidence: 89%

Recent Advancements in Hematology: Knowledge, Methods and Dissemination, Part 1

Fitzgibbon

Park

Cook

et al. 2020

Hemato

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“…In this study we show that IL-32 is expressed by a fraction of MM cells and that it promotes survival and proliferation of these cells. IL-32 is also expressed by regulatory or senescent/exhausted T cells in MM, but if/how this affects the function of the T-cells is not known 50, 51 . IL-32 is secreted from the MM cells and IL-32 in the BM microenvironment enhance osteoclast differentiation 15 , it can promote IL-6 production from stromal cells 52 and may generate immunosuppressive macrophages, 53 all factors that may lead to a more aggressive disease development.…”

Section: Discussionmentioning

confidence: 99%

IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

Aass

Mjelle

Kastnes

et al. 2021

Preprint

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IL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.

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Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma

Cited by 245 publications

References 63 publications

Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

Recent Advancements in Hematology: Knowledge, Methods and Dissemination, Part 1

IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

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