Delaney K Geitgey, Miyoung Lee, Kirsten A Cottrill, Maya Jaffe, William Pilcher, Swati Bhasin, Jessica Randall, Anthony J Ross, Michelle Salemi, Marisol Castillo-Castrejon, Matthew B Kilgore, Ayjha C Brown, Jeremy M Boss, Rich Johnston, Anne M Fitzpatrick, Melissa L Kemp, Robert English, Eric Weaver, Pritha Bagchi, Ryan Walsh, Christopher D Scharer, Manoj Bhasin, Joshua D Chandler, Karmella A Haynes, Elizabeth A Wellberg, Curtis J Henry
{"title":"The 'omics of obesity in B-cell acute lymphoblastic leukemia.","authors":"Delaney K Geitgey, Miyoung Lee, Kirsten A Cottrill, Maya Jaffe, William Pilcher, Swati Bhasin, Jessica Randall, Anthony J Ross, Michelle Salemi, Marisol Castillo-Castrejon, Matthew B Kilgore, Ayjha C Brown, Jeremy M Boss, Rich Johnston, Anne M Fitzpatrick, Melissa L Kemp, Robert English, Eric Weaver, Pritha Bagchi, Ryan Walsh, Christopher D Scharer, Manoj Bhasin, Joshua D Chandler, Karmella A Haynes, Elizabeth A Wellberg, Curtis J Henry","doi":"10.1093/jncimonographs/lgad014","DOIUrl":null,"url":null,"abstract":"<p><p>The obesity pandemic currently affects more than 70 million Americans and more than 650 million individuals worldwide. In addition to increasing susceptibility to pathogenic infections (eg, SARS-CoV-2), obesity promotes the development of many cancer subtypes and increases mortality rates in most cases. We and others have demonstrated that, in the context of B-cell acute lymphoblastic leukemia (B-ALL), adipocytes promote multidrug chemoresistance. Furthermore, others have demonstrated that B-ALL cells exposed to the adipocyte secretome alter their metabolic states to circumvent chemotherapy-mediated cytotoxicity. To better understand how adipocytes impact the function of human B-ALL cells, we used a multi-omic RNA-sequencing (single-cell and bulk transcriptomic) and mass spectroscopy (metabolomic and proteomic) approaches to define adipocyte-induced changes in normal and malignant B cells. These analyses revealed that the adipocyte secretome directly modulates programs in human B-ALL cells associated with metabolism, protection from oxidative stress, increased survival, B-cell development, and drivers of chemoresistance. Single-cell RNA sequencing analysis of mice on low- and high-fat diets revealed that obesity suppresses an immunologically active B-cell subpopulation and that the loss of this transcriptomic signature in patients with B-ALL is associated with poor survival outcomes. Analyses of sera and plasma samples from healthy donors and those with B-ALL revealed that obesity is associated with higher circulating levels of immunoglobulin-associated proteins, which support observations in obese mice of altered immunological homeostasis. In all, our multi-omics approach increases our understanding of pathways that may promote chemoresistance in human B-ALL and highlight a novel B-cell-specific signature in patients associated with survival outcomes.</p>","PeriodicalId":73988,"journal":{"name":"Journal of the National Cancer Institute. Monographs","volume":"2023 61","pages":"12-29"},"PeriodicalIF":0.0000,"publicationDate":"2023-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10157791/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of the National Cancer Institute. Monographs","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/jncimonographs/lgad014","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
The obesity pandemic currently affects more than 70 million Americans and more than 650 million individuals worldwide. In addition to increasing susceptibility to pathogenic infections (eg, SARS-CoV-2), obesity promotes the development of many cancer subtypes and increases mortality rates in most cases. We and others have demonstrated that, in the context of B-cell acute lymphoblastic leukemia (B-ALL), adipocytes promote multidrug chemoresistance. Furthermore, others have demonstrated that B-ALL cells exposed to the adipocyte secretome alter their metabolic states to circumvent chemotherapy-mediated cytotoxicity. To better understand how adipocytes impact the function of human B-ALL cells, we used a multi-omic RNA-sequencing (single-cell and bulk transcriptomic) and mass spectroscopy (metabolomic and proteomic) approaches to define adipocyte-induced changes in normal and malignant B cells. These analyses revealed that the adipocyte secretome directly modulates programs in human B-ALL cells associated with metabolism, protection from oxidative stress, increased survival, B-cell development, and drivers of chemoresistance. Single-cell RNA sequencing analysis of mice on low- and high-fat diets revealed that obesity suppresses an immunologically active B-cell subpopulation and that the loss of this transcriptomic signature in patients with B-ALL is associated with poor survival outcomes. Analyses of sera and plasma samples from healthy donors and those with B-ALL revealed that obesity is associated with higher circulating levels of immunoglobulin-associated proteins, which support observations in obese mice of altered immunological homeostasis. In all, our multi-omics approach increases our understanding of pathways that may promote chemoresistance in human B-ALL and highlight a novel B-cell-specific signature in patients associated with survival outcomes.