The 'omics of obesity in B-cell acute lymphoblastic leukemia.
Delaney K GeitgeyMiyoung LeeKirsten A CottrillMaya JaffeWilliam PilcherSwati BhasinJessica RandallAnthony J RossMichelle SalemiMarisol Castillo-CastrejonMatthew B KilgoreAyjha C BrownJeremy M BossRich JohnstonAnne M FitzpatrickMelissa L KempRobert EnglishEric WeaverPritha BagchiRyan WalshChristopher D ScharerManoj BhasinJoshua D ChandlerKarmella A HaynesElizabeth A WellbergCurtis J HenryPublished in: Journal of the National Cancer Institute. Monographs (2023)
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.
Keyphrases
- single cell
- insulin resistance
- high fat diet induced
- rna seq
- induced apoptosis
- weight loss
- adipose tissue
- acute lymphoblastic leukemia
- metabolic syndrome
- sars cov
- endothelial cells
- high throughput
- type diabetes
- cell cycle arrest
- oxidative stress
- weight gain
- skeletal muscle
- signaling pathway
- pluripotent stem cells
- squamous cell carcinoma
- pi k akt
- induced pluripotent stem cells
- public health
- dna damage
- endoplasmic reticulum stress
- drug resistant
- cell proliferation
- end stage renal disease
- single molecule
- coronavirus disease
- papillary thyroid
- risk factors
- respiratory syndrome coronavirus
- coronary artery disease
- prognostic factors
- cell death
- free survival
- solid state
- chronic kidney disease
- lymph node metastasis
- peritoneal dialysis