PTEN Counter Balances mTORC1 and PI3K Activities to Maintain Metabolic Homeostasis of B-ALL

Abstract

Significance PIK3CA activating mutations and PTEN deletions are frequent in nearly all types of cancer but hardly detected in B cell acute lymphoblastic leukemia (B-ALL). Our study revealed unexpected energy crisis in terms of ATP deficit and oxidative phosphorylation (OXPHOS) impairment in Pten depleted B-ALL cells. Strikingly, a significant reduction of MYC levels as well as cell viability were observed in both murine and human B-ALL cells with PI3K hyperactivation. Furthermore, forced MYC expression not only recovered cell survival but also lifted restriction of mTORC1 signaling in Pten deficient B-ALL cells. Here we reported unique crosstalk of PI3K and mTORC1 activities which is mediated by MYC to ensure balanced cellular energy supply and anabolism in B-ALL cells. Results We revealed the essentiality of PTEN in ALL cells was through keeping energy production by glutaminolysis. Seahorse analysis and glutamine consumption assay showed significant half-fold reduction of both oxygen consumption rate and glutamine utilization in Pten KO ALL cells. Importantly, these defects were fully rescued by ectopic expression of MYC which drastically increased cell mass and proliferation of Pten KO B-ALL cells. By overexpressing the Myc T58A mutant, which is resistant to proteasomal degradation, we found a further 2-fold enhancement of cell growth compared to wild-type Myc in Pten KO ALL cells. We further demonstrated that the half-life of Myc in Pten KO cells was significantly shortened through proteasomal degradation, suggesting the loss of Pten disrupted Myc stability. Based on the transcriptomic profiling of Pten deficient ALL cells, we found that PI3K hyperactivation decreased multiple cellular biosynthetic processes, while Myc overexpression significantly restored biosynthesis, indicating a potential role of Myc in preserving anabolic activity. Untargeted metabolomic analysis indicated depletion of amino acid levels in Pten KO murine B-ALL cells, while Myc overexpression partially restored these levels. We further demonstrated arginine, one of the amino acids that sensed by mTORC1, was significantly enriched in MYC overexpressed Pten KO ALL cells and mediated mTORC1 full activation. Those results indicate the pivotal function of Myc in synergizing PI3K and mTORC1 signaling to promote oncogenic metabolism of B-ALL. Conclusion In summary, our study revealed the essential function of PTEN in maintaining cellular metabolic homeostasis through antagonizing PI3K hyperactivation in B-ALL. We further demonstrated that MYC levels was leveraged by PI3K signaling to prevent mTORC1 activation and further biosynthetic elevation. PI3K hyperactivation was found to deplete energy reserve and restrain biomass accumulation, which destructs metabolic adaptation to oncogenic proliferation in B-ALL cells. Our findings decipher a unique synthetic vulnerability of PI3K and MYC in malignant precursor B cells and highlight the balance between anabolism and energy supply for cell survival as a promising therapeutic strategy for B-ALL.