Trascriptomic profiling of AML cell lines with genetic inactivation of B56α regulatory subunit of PP2A

Drug-resistant leukemia cells use different metabolic substrates to rewire their metabolism and rely on oxidative phosphorylation (OXPHOS) for energy production. Therefore, impairing this dependent mechanism of energy metabolism represents an exciting strategy to face this unmet clinical need.

Here, through leveraging unbiased multi-omics-based approaches, combining transcriptomic and proteomic analyses, and validating our observations using both genetic and pharmacological tools, we have defined key new roles for the tumor suppressor PP2A-B56α complex in regulating OXPHOS and treatment response in disease-relevant AML models. From a translational perspective, the specific stabilization of PP2A-B56α complexes with a novel PP2A molecular glue reduces OXPHOS levels in treatment-resistant AML cell lines and improves treatment response in both Ven-Aza-sensitive and -resistant AML cell lines, primary cells, and in vivo models.