Adipocyte-mediated epigenomic instability in human T-ALL cells is cytotoxic and phenocopied by epigenetic-modifying drugs

• Authors: Miyoung Lee, Emory University; Delaney KK Geitgey, Emory University; Jamie AG Hamilton, Emory University; Jeremy Boss, Emory University; Christopher Scharer, Emory University; Jennifer Spangle, Emory University; Karmella Haynes, Emory University; Curtis Henry, Emory University
• Journal Title: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
• Volume: Volume 10
• Publisher: FRONTIERS MEDIA SA | 2022-08-19, Pages 909557-909557
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3389/fcell.2022.909557
• Subjects: Health Sciences, Immunology; Biology, Microbiology; Engineering, Biomedical
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; Developmental Biology; obesity; leukemia; epigenetics; cell cycle; genotoxic stress; ACUTE LYMPHOBLASTIC-LEUKEMIA; DNA-DAMAGE RESPONSE; RNA-POLYMERASE-II; BODY-MASS INDEX; INDUCTION THERAPY; INDUCED APOPTOSIS; UNITED-STATES; OBESITY; CANCER; MECHANISMS

Abstract

The world’s population with obesity is reaching pandemic levels. If current trends continue, it is predicted that there will be 1.5 billion people with obesity by 2030. This projection is alarming due to the association of obesity with numerous diseases including cancer, with recent studies demonstrating a positive association with acute myeloid leukemia (AML) and B cell acute lymphoblastic leukemia (B-ALL). Interestingly, several epidemiological studies suggest the converse relationship may exist in patients with T cell acute lymphoblastic leukemia (T-ALL). To determine the relationship between obesity and T-ALL development, we employed the diet-induced obesity (DIO) murine model and cultured human T-ALL cells in adipocyte-conditioned media (ACM), bone marrow stromal cell-conditioned media, stromal conditioned media (SCM), and unconditioned media to determine the functional impact of increased adiposity on leukemia progression. Whereas only 20% of lean mice transplanted with T-ALL cells survived longer than 3 months post-inoculation, 50%–80% of obese mice with leukemia survived over this same period. Furthermore, culturing human T-ALL cells in ACM resulted in increased histone H3 acetylation (K9/K14/K18/K23/K27) and methylation (K4me3 and K27me3) posttranslational modifications (PTMs), which preceded accelerated cell cycle progression, DNA damage, and cell death. Adipocyte-mediated epigenetic changes in human T-ALL cells were recapitulated with the H3K27 demethylase inhibitor GSK-J4 and the pan-HDAC inhibitor vorinostat. These drugs were also highly cytotoxic to human T-ALL cells at low micromolar concentrations. In summary, our data support epidemiological studies demonstrating that adiposity suppresses T-ALL pathogenesis. We present data demonstrating that T-ALL cell death in adipose-rich microenvironments is induced by epigenetic modifications, which are not tolerated by leukemia cells. Similarly, GSK-J4 and vorinostat treatment induced epigenomic instability and cytotoxicity profiles that phenocopied the responses of human T-ALL cells to ACM, which provides additional support for the use of epigenetic modifying drugs as a treatment option for T-ALL.