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

Miyoung Lee; Delaney K Geitgey; Jamie A G Hamilton; Jeremy M Boss; Christopher D Scharer; Jennifer M Spangle; Karmella A Haynes; Curtis J Henry

doi:10.3389/fcell.2022.909557

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

Front Cell Dev Biol. 2022 Aug 19:10:909557. doi: 10.3389/fcell.2022.909557. eCollection 2022.

Authors

Miyoung Lee¹, Delaney K Geitgey¹, Jamie A G Hamilton¹, Jeremy M Boss², Christopher D Scharer², Jennifer M Spangle^{3

4}, Karmella A Haynes⁵, Curtis J Henry^{1

3}

Affiliations

¹ Department of Pediatrics, Emory University School of Medicine and Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, United States.
² Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, United States.
³ Winship Cancer Institute, Atlanta, GA, United States.
⁴ Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, United States.
⁵ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States.

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.

Keywords: cell cycle; epigenetics; genotoxic stress; leukemia; obesity.