The effect of TRAF6 loss on the gene expression profiles in leukemia cells II

Although altered TRAF6 expression is observed in human acute myeloid leukemia (AML), its role in the AML pathogenesis remains elusive. In this study, we showed that the loss of TRAF6 in AML cells significantly impairs leukemic function in vitro and in vivo, indicating its functional importance in AML subsets. Loss of TRAF6 induces metabolic alterations, such as changes in glycolysis as well as impaired mitochondrial membrane potential and respiratory capacity. The restoration of growth capacity and metabolic activity in leukemic cells with TRAF6 loss, achieved through either forced expression of OGT or pharmacological inhibition of O-GlcNAcase (OGA) that removes O-GlcNAc, indicates the significant role of O-GlcNAc modification in the TRAF6-related cellular and metabolic dynamics. Our findings highlight the oncogenic function of TRAF6 in leukemia and illuminate the novel TRAF6/OGT/O-GlcNAc axis as a potential regulator of metabolic reprogramming in leukemogenesis. Overall design: To examine the role of TRAF6 in AML cells, we established TF-1, MOLM14 and THP-1 cells transduced with the inducible shTRAF6. In addition, Traf6fl/fl mice were crossed with R26-CreERT2 mice for inducible deletion. Traf6+/+;R26-CreERT2 and Traf6fl/fl;R26-CreERT2 lineage negative bone marrow cells from C57Bl/6 mice were transduced with retrovirus encoding MLL-AF9.