Bruton’s tyrosine kinase is at the crossroads of metabolic adaptation in primary malignant human lymphocytes

Sharif-Askari, Bahram; Doyon, D; Paliouras, Miltiadis; Aloyz, Raquel

doi:10.1038/s41598-019-47305-2

Cited by 13 publications

(8 citation statements)

References 38 publications

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“…We extend these findings with the observations that patients with mitochondrial complex deficiency or healthy individuals exposed to BTKi, exhibit diminished B-cell mitochondrial respiration and modulated effector responses, without decreased viability or loss of major circulating cell subsets. Our finding, both in vitro and in vivo , that inhibition of BTK (and associated inhibition of mitochondrial respiration) does not significantly impact survival of normal B cells, points to fundamental differences in the roles of BTK and metabolic regulation of normal B cells as compared to neoplastic B cells, where BTKi is known to impact cell survival [ 50 ]. Indeed, in healthy individuals and in patients with MS, rather than decreasing B-cell counts, treatment with BTKi appears to transiently increase B-cell counts [ 4 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

BTK inhibition limits B-cell–T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy

Tang

Burns

et al. 2022

Acta Neuropathol

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Inhibition of Bruton’s Tyrosine Kinase (BTKi) is now viewed as a promising next-generation B-cell-targeting therapy for autoimmune diseases including multiple sclerosis (MS). Surprisingly little is known; however, about how BTKi influences MS disease-implicated functions of B cells. Here, we demonstrate that in addition to its expected impact on B-cell activation, BTKi attenuates B-cell:T-cell interactions via a novel mechanism involving modulation of B-cell metabolic pathways which, in turn, mediates an anti-inflammatory modulation of the B cells. In vitro, BTKi, as well as direct inhibition of B-cell mitochondrial respiration (but not glycolysis), limit the B-cell capacity to serve as APC to T cells. The role of metabolism in the regulation of human B-cell responses is confirmed when examining B cells of rare patients with mitochondrial respiratory chain mutations. We further demonstrate that both BTKi and metabolic modulation ex vivo can abrogate the aberrant activation and costimulatory molecule expression of B cells of untreated MS patients. Finally, as proof-of-principle in a Phase 1 study of healthy volunteers, we confirm that in vivo BTKi treatment reduces circulating B-cell mitochondrial respiration, diminishes their activation-induced expression of costimulatory molecules, and mediates an anti-inflammatory shift in the B-cell responses which is associated with an attenuation of T-cell pro-inflammatory responses. These data collectively elucidate a novel non-depleting mechanism by which BTKi mediates its effects on disease-implicated B-cell responses and reveals that modulating B-cell metabolism may be a viable therapeutic approach to target pro-inflammatory B cells.

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Section: Discussionmentioning

confidence: 99%

BTK inhibition limits B-cell–T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy

Tang

Burns

et al. 2022

Acta Neuropathol

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“… 128 and Table 3 ); BTK inhibition can inhibit free fatty acid metabolism in chronic lymphocytic leukemia through reduction of lipoprotein lipase ( 129 ). Furthermore, crosstalk between BTK signaling and bioenergetic stress responses in leukemic B cells suggests that cellular metabolic rewiring could mediate the metabolic effects of these molecules ( 130 ). Multiple BTK inhibitors are currently in clinical trials for AIRDs.…”

Section: Target Synthetic Dmardsmentioning

confidence: 99%

Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies

Robinson¹,

Pineda-Torra²,

Ciurtin³

et al. 2022

Journal of Clinical Investigation

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Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed.

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“…LTME produces various essential proteins and metabolites [ 3 , 17 ] modulating the redox and metabolic state of CLL cells [ 18 ] and switching either to oxidative phosphorylation (OXPHOS) or glycolysis [ 19 ]. Furthermore, enhanced BCR signaling induces the metabolic activation of CLL cells through OXPHOS, energetically supporting the transcription and translation processes [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Proteomics and Drug Repurposing in CLL towards Precision Medicine

Mavridou

Psatha

Aivaliotis

2021

Cancers

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CLL is a hematological malignancy considered as the most frequent lymphoproliferative disease in the western world. It is characterized by high molecular heterogeneity and despite the available therapeutic options, there are many patient subgroups showing the insufficient effectiveness of disease treatment. The challenge is to investigate the individual molecular characteristics and heterogeneity of these patients. Proteomics analysis is a powerful approach that monitors the constant state of flux operators of genetic information and can unravel the proteome heterogeneity and rewiring into protein pathways in CLL patients. This review essences all the available proteomics studies in CLL and suggests the way these studies can be exploited to find effective therapeutic options combined with drug repurposing approaches. Drug repurposing utilizes all the existing knowledge of the safety and efficacy of FDA-approved or investigational drugs and anticipates drug alignment to crucial CLL therapeutic targets, leading to a better disease outcome. The drug repurposing studies in CLL are also discussed in this review. The next goal involves the integration of proteomics-based drug repurposing in precision medicine, as well as the application of this procedure into clinical practice to predict the most appropriate drugs combination that could ensure therapy and the long-term survival of each CLL patient.

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Bruton’s tyrosine kinase is at the crossroads of metabolic adaptation in primary malignant human lymphocytes

Cited by 13 publications

References 38 publications

BTK inhibition limits B-cell–T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy

BTK inhibition limits B-cell–T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy

Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies

Proteomics and Drug Repurposing in CLL towards Precision Medicine

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