High Mitophagy and Low Glycolysis Predict Better Clinical Outcomes in Acute Myeloid Leukemias

Acute myeloid leukemia (AML) emerges as one of the most common and fatal leukemias. Treatment of the disease remains highly challenging owing to profound metabolic rewiring mechanisms that confer plasticity to AML cells, ultimately resulting in therapy resistance. Autophagy, a highly conserved lysosomal-driven catabolic process devoted to macromolecular turnover, displays a dichotomous role in AML by suppressing or promoting disease development and progression. Glycolytic metabolism represents a pivotal strategy for AML cells to sustain increasing energy needs related to uncontrolled growth during disease progression. In this study, we tested the hypothesis that a high glycolytic rate and low autophagy flux could represent an advantage for AML cell proliferation and thus be detrimental for patient's prognosis, and vice versa. TCGA in silico analysis of the AML cohort shows that the high expression of <i>MAP1LC3B</i> (along with that of <i>BECN1</i> and with low expression of <i>p62</i>/<i>SQSTM1</i>) and the high expression of <i>BNIP3</i> (along with that of <i>PRKN</i> and of <i>MAP1LC3B</i>), which together are indicative of increased autophagy and mitophagy, correlate with better prognosis. On the other hand, the high expression of glycolytic markers <i>HK2</i>, <i>PFKM</i>, and <i>PKM</i> correlates with poor prognosis. Most importantly, the association of a low expression of glycolytic markers with a high expression of autophagy-mitophagy markers conferred the longest overall survival for AML patients. Transcriptomic analysis showed that this combined signature correlates with the downregulation of a subset of genes required for the differentiation of myeloid cells, lactate/pyruvate transporters, and cell cycle progression, in parallel with the upregulation of genes involved in autophagy/lysosomal trafficking and proteolysis, anti-tumor responses like beta-interferon production, and positive regulation of programmed cell death. Taken together, our data support the view that enhanced autophagy-mitophagy flux together with low glycolytic rate predisposes AML patients to a better clinical outcome, suggesting that autophagy inducers and glucose restrictors may hold potential as adjuvant therapeutics for improving AML management.