Integration of Metabolomics and Gene Expression Profiling Elucidates IL4I1 as Modulator of Ibrutinib Resistance in ABC-Diffuse Large B Cell Lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). B-cell NHLs rely on Bruton’s tyrosine kinase (BTK) mediated B-cell receptor signaling for survival and disease progression. However, they are often resistant to BTK inhibitors or soon acquire resistance after drug exposure resulting in the drug-tolerant form. The drug-tolerant clones proliferate faster, have increased metabolic activity, and shift to oxidative phosphorylation; however, how this metabolic programming occurs in the drug-resistant tumor is poorly understood. In this study, we explored for the first time the metabolic regulators of ibrutinib-resistant activated B-cell (ABC) DLBCL using a multi-omics analysis that integrated metabolomics (using high-resolution mass spectrometry) and transcriptomic (gene expression analysis). Overlay of the unbiased statistical analyses, genetic perturbation, and pharmaceutical inhibition was further used to identify the key players contributing to the metabolic reprogramming of the drug-resistant clone. Gene-metabolite integration revealed interleukin four induced 1 (IL4I1) at the crosstalk of two significantly altered metabolic pathways involved in producing various amino acids. We showed for the first time that drug-resistant clones undergo metabolic reprogramming towards oxidative phosphorylation and are modulated via the BTK-PI3K-AKT-IL4I1 axis. Our report shows how these cells become dependent on PI3K/AKT signaling for survival after acquiring ibrutinib resistance and shift to sustained oxidative phosphorylation; additionally, we outline the compensatory pathway that might regulate this metabolic reprogramming in the drug-resistant cells. These findings from our unbiased analyses highlight the role of metabolic reprogramming during drug resistance development. Our work demonstrates that a multi-omics approach can be a robust and impartial strategy to uncover genes and pathways that drive metabolic deregulation in cancer cells.

Adaptive Metabolism of Staphylococcus aureus Revealed by Untargeted Metabolomics

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Untargeted metabolomics and transcriptomics identified glutathione metabolism disturbance and PCS and TMAO as potential biomarkers for ER stress in lung

“…Metabolomics and transcriptomics are two methods of profiling that have been frequently used to provide information regarding pathological phenotypes 8 or for the aim of pathogenesis studies 9 , drug-target identification 10 , and biomarker recognition 11 etc. Liquid chromatography–mass spectrometry (LC–MS), as a robust and informative tool in identifying and quantifying molecules in mixtures, could be used to get reliable data regarding the metabolites in tissues, making metabolic comparison between phenotypes possible.…”

Expression of Tryptophan Metabolism Enzymes in Patients with Diffuse Large B‐cell Lymphoma and NK/T‐cell Lymphoma

“…Moreover, high IL4I1 expression was associated with the absence of bone marrow involvement and a better outcome. Choueiry et al integrated metabolomics and gene expression profiling and elucidated IL4I1 as a modulator of ibrutinib resistance in activated B‐cell (ABC) DLBCL 38 . Therefore, further investigation is required to confirm the roles and explore the potential mechanisms of IL4I1 in DLBCL and NK/TCL in future studies.…”