Integration of Metabolomics and Gene Expression Profiling Elucidates IL4I1 as Modulator of Ibrutinib Resistance in ABC-Diffuse Large B Cell Lymphoma
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 e...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/9/2146 |
| _version_ | 1797535755352932352 |
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| author | Fouad Choueiry Satishkumar Singh Anuvrat Sircar Georgios Laliotis Xiaowei Sun Evangelia Chavdoula Shiqi Zhang JoBeth Helmig-Mason Amber Hart Narendranath Epperla Philip Tsichlis Robert Baiocchi Lapo Alinari Jiangjiang Zhu Lalit Sehgal |
| author_facet | Fouad Choueiry Satishkumar Singh Anuvrat Sircar Georgios Laliotis Xiaowei Sun Evangelia Chavdoula Shiqi Zhang JoBeth Helmig-Mason Amber Hart Narendranath Epperla Philip Tsichlis Robert Baiocchi Lapo Alinari Jiangjiang Zhu Lalit Sehgal |
| author_sort | Fouad Choueiry |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T11:49:50Z |
| format | Article |
| id | doaj.art-127e6c2fc4c94db98d91d6d9a24ade52 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:49:50Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-127e6c2fc4c94db98d91d6d9a24ade522023-11-21T17:46:07ZengMDPI AGCancers2072-66942021-04-01139214610.3390/cancers13092146Integration of Metabolomics and Gene Expression Profiling Elucidates IL4I1 as Modulator of Ibrutinib Resistance in ABC-Diffuse Large B Cell LymphomaFouad Choueiry0Satishkumar Singh1Anuvrat Sircar2Georgios Laliotis3Xiaowei Sun4Evangelia Chavdoula5Shiqi Zhang6JoBeth Helmig-Mason7Amber Hart8Narendranath Epperla9Philip Tsichlis10Robert Baiocchi11Lapo Alinari12Jiangjiang Zhu13Lalit Sehgal14Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USADivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USAJames Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USADepartment of Human Sciences, The Ohio State University, Columbus, OH 43210, USAJames Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USADepartment of Human Sciences, The Ohio State University, Columbus, OH 43210, USADivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USAJames Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USADivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Human Sciences, The Ohio State University, Columbus, OH 43210, USADivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADiffuse 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.https://www.mdpi.com/2072-6694/13/9/2146DLBCLlymphomatranscriptomicmetabolomicsdrug resistanceibrutinib |
| spellingShingle | Fouad Choueiry Satishkumar Singh Anuvrat Sircar Georgios Laliotis Xiaowei Sun Evangelia Chavdoula Shiqi Zhang JoBeth Helmig-Mason Amber Hart Narendranath Epperla Philip Tsichlis Robert Baiocchi Lapo Alinari Jiangjiang Zhu Lalit Sehgal Integration of Metabolomics and Gene Expression Profiling Elucidates IL4I1 as Modulator of Ibrutinib Resistance in ABC-Diffuse Large B Cell Lymphoma Cancers DLBCL lymphoma transcriptomic metabolomics drug resistance ibrutinib |
| title | Integration of Metabolomics and Gene Expression Profiling Elucidates IL4I1 as Modulator of Ibrutinib Resistance in ABC-Diffuse Large B Cell Lymphoma |
| title_full | Integration of Metabolomics and Gene Expression Profiling Elucidates IL4I1 as Modulator of Ibrutinib Resistance in ABC-Diffuse Large B Cell Lymphoma |
| title_fullStr | Integration of Metabolomics and Gene Expression Profiling Elucidates IL4I1 as Modulator of Ibrutinib Resistance in ABC-Diffuse Large B Cell Lymphoma |
| title_full_unstemmed | Integration of Metabolomics and Gene Expression Profiling Elucidates IL4I1 as Modulator of Ibrutinib Resistance in ABC-Diffuse Large B Cell Lymphoma |
| title_short | Integration of Metabolomics and Gene Expression Profiling Elucidates IL4I1 as Modulator of Ibrutinib Resistance in ABC-Diffuse Large B Cell Lymphoma |
| title_sort | integration of metabolomics and gene expression profiling elucidates il4i1 as modulator of ibrutinib resistance in abc diffuse large b cell lymphoma |
| topic | DLBCL lymphoma transcriptomic metabolomics drug resistance ibrutinib |
| url | https://www.mdpi.com/2072-6694/13/9/2146 |
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