MondoA mediates in vivo aggressiveness of common ALL and may serve as a T cell immunotherapy target

Oncogene addiction provides ideal targets for immunotherapy. We previously showed that the high expression of the conserved transcription factor MondoA mediates glucose consumption and stemness of a cALL cell line. We now report the expression of MondoA (MLXIP) in cALL compared to other malignancies, its role in malignancy of cALL in vivo, downstream pathways and correlation with relapse risk. Given the non-accessibility of transcription factors by drugs or chimeric antigen receptor transgenic T cells, we assessed the targetability of MondoA by allo-restricted, peptide-specific T cells. We found MondoA to be most highly expressed in pediatric cALL. MondoA knock down (KD) in cALL cell lines and their subsequent analysis in xenograft mice reduced the number of leukemic blasts in blood, marrow and spleen. Spleen size and weight normalized in mice after MondoA KD. Consistent with these data, MondoA overexpression correlated with relapse risk in cALL patients, as its expression was 63% higher in the very high-risk group relative to the non-high-risk group. Transcriptomic profiling of cALL cell lines after MondoA KD revealed an induction of aerobic glycolysis switch genes and hypoxia-response by MondoA. Indeed, MondoA appeared to be required for HIF1A protein stabilization. Therapeutically, MondoA-derived peptide antigens and HLA-A*02:01+ cALL lines were successfully recognized and killed by specific, allo-restricted CD8+ T cells. In conclusion, our findings demonstrate that MondoA maintains leukemic burden and aggressiveness of cALL in vivo possibly by modulating metabolic and hypoxia stress response. Moreover, we identified MondoA as a promising target for immunotherapy of cALL.

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