Abstract B51: Adaptation to oncogene-induced metabolic stress by MondoA (MLXIP) drives common acute lymphoblastic leukemia (cALL) malignancy

Abstract

Abstract MondoA (also known as MLXIP, MAX-like protein X interacting protein) is a metabolic stress sensor and a proglycolytic transcription factor potentially involved in metabolic addiction features of leukemia and the Warburg effect. MondoA dimerizes with MLX within the MYC interactome and promotes longevity in C. elegans (Johnson et al., 2014). The MYC interactome comprises the MYC/MAX/MNT/MLX/MLXIP transcription factor network: Its key players MYC, MNT and MLXIP differentially mediate proliferation, differentiation, or metabolism by heterodimerization with MAX or MLX. We previously described MondoA to promote malignancy of common precursor B-cell acute lymphoblastic leukemia (cALL). MondoA knockdown (MKD) in cALL cell lines in xenografted mice reduced the number of leukemic blasts (Sipol, 2014). Here we report that MondoA high expression was observed in ALL subtypes with no MYC overexpression. RNA-sequencing data of 132 primary ALL bone marrow samples confirmed the inverse correlation of MYC and MondoA. Interestingly, in subgroups of ALL with low MYC expression and high MondoA (cALL with BCR-ABL, cALL with TCF3-PBX, cALL with ETV6-RUNX1, and cALL with hyperdiploid karyotype), metabolic gene sets did not appear as upregulated. In contrast, cALL samples with high MYC expression and low MondoA (proB-ALL with MLL rearrangements and B-ALL with IGH-MYC fusion gene) demonstrated upregulation of pathways for oxidative phosphorylation and fatty acid metabolism in addition to targets of E2F, G2M checkpoints, and MYC targets. Using CRISPR/CAS9-mediated knockout (MKO), we demonstrate that MondoA dials down MYC-induced metabolic stress and increases leukemia stress resistance. By limiting mitochondrial pyruvate dehydrogenase (PDH) activity in PDHK1 (pyruvate dehydrogenase kinase 1)-dependent manner, MondoA decreases oxidative phosphorylation. In line with limiting effect of MondoA on oxidative phosphorylation, we observed that MondoA decreases ROS generation in B cells. In conclusion, MondoA is restricting MYC-target gene expression to promote leukemia cell survival by facilitating glycolysis and adaption to oxidative stress. MondoA limits pyruvate availability for the TCA cycle by decreasing PDH activity, thus ensuring consistent glycolytic flux, mediating the Warburg effect, and insuring integrity of leukemia metabolism and ROS balancing in response to oncogene activation. Citation Format: Alexandra Sipol, Erik Hameister, Andreas Petry, Agnes Görlach, Jürgen Ruland, Guenther Richter, Stefan Burdach, Poul Sorensen. Adaptation to oncogene-induced metabolic stress by MondoA (MLXIP) drives common acute lymphoblastic leukemia (cALL) malignancy [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B51.