GSE168864
MondoA Drives Malignancy in B-ALL through Enhanced Adaptation to Metabolic Stress [ChIP-seq]
MondoA (also known as MLXIP), a member of the MYC interactome, has been described as an example of a metabolic sensor. By assessing patient data sets we found that MondoA overexpression is associated with a worse survival in pediatric common acute lymphoblastic leukemia (B-ALL). Using CRISPR/Cas9 and RNA interference approaches, we observed that MondoA depletion reduces transformational capacity of B-ALL cells in vitro and dramatically inhibits malignant potential in an in vivo mouse model. Interestingly, reduced expression of MondoA in patient data sets correlated with enrichment in metabolic pathways. The loss of MondoA correlated with increased tricarboxylic acid (TCA) cycle activity. Mechanistically, MondoA senses metabolic stress in B-ALL cells by restricting oxidative phosphorylation through reduced PDH activity. Glutamine starvation conditions greatly enhance this effect and highlight the inability to mitigate metabolic stress upon loss of MondoA in B-ALL. CHIPseq revealed a modest but highly significant redistribution of MYC towards binding sites shared with MondoA upon loss of MondoA. Overall design: ChIP-seq of MYC and MondoA TF in MondoA-WT and MondoA-KO Nalm6 cells