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

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.

Obesity, bone marrow adiposity, and leukemia: Time to act

“…299 However, another study has indicated that obesity negatively affects T-ALL in mice models by inducing their apoptosis through epigenetic modification (histone H3 acetylation and methylation), which is inhibited by H3K27 demethylase inhibitor GSK-J4 and the pan-HDAC inhibitor vorinostat. 300 Notably, fasting does not affect AML initiation and progression. Details of fasting and dietary interventions in different cancers have been discussed elsewhere.…”

“…Furthermore, fasting alone robustly inhibits the initiation of ALL (B‐ALL and T‐ALL) and reverses their progression in mice and human xenograft models by upregulating LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1) and insulin growth factor‐1 binding protein B1 (IGFB1), but decreasing the high circulating and BM leptin and IGF‐1 level 299 . However, another study has indicated that obesity negatively affects T‐ALL in mice models by inducing their apoptosis through epigenetic modification (histone H3 acetylation and methylation), which is inhibited by H3K27 demethylase inhibitor GSK‐J4 and the pan‐HDAC inhibitor vorinostat 300 . Notably, fasting does not affect AML initiation and progression.…”

Emodin inhibits bladder inflammation and fibrosis in mice with interstitial cystitis by regulating JMJD3

“…1a). GSK-J4 is a small-molecule inhibitor functions on H3K27 histone demethylase JMJD3/UTX to suppress enzyme activity 29,30 . Subsequently, quantify immunofluorescence staining results also proved this phenomenon again (Figs.…”