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

ABSTRACT: Deregulation of mitochondrial metabolism is one of the main mechanisms of resistance to the approved venetoclax-azacitidine (Ven-Aza) combination therapy in Acute Myeloid Leukemia (AML), limiting the outcomes for these cohort of patients. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291351 | GEO | 2026/09/04

REPOSITORIES: GEO

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Project description:Deregulated apoptosis signaling is characteristic for many cancers and contributes to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Apoptosis is controlled by different pro- and anti-apoptotic molecules. Inhibition of anti-apoptotic molecules like B-cell lymphoma 2 (BCL-2) has been developed as therapeutic strategy. Venetoclax (VEN), a selective BCL-2 inhibitor has shown clinical activity in different lymphoid malignancies and is currently evaluated in first clinical trials in BCP-ALL. However, insensitivity to VEN has been described constituting a major clinical concern. Here, we addressed and modeled VEN-resistance in BCP-ALL, investigated the underlying mechanisms in cell lines and patient-derived xenograft (PDX) samples and identified potential strategies to overcome VEN-insensitivity. Leukemia lines with VEN-specific resistance were generated in vitro and further characterized using RNA-seq analysis. Interestingly, gene sets annotated to the citric/tricarboxylic acid cycle and the respiratory electron transport chain were significantly enriched and upregulated, indicating increased mitochondrial metabolism in VEN-resistant ALL. Metabolic profiling showed sustained high mitochondrial metabolism in VEN-resistant lines as compared to control lines. Adccordingly, primary PDX-ALL samples with intrinsic VEN-insensitivity showed higher oxygen consumption and ATP production rates, further highlighting that increased mitochondrial activity is a characteristic feature of VEN-resistant ALL. VEN-resistant PDX-ALL showed significant higher mitochondrial DNA content and differed in mitochondria morphology with significantly larger and elongated structures, further corroborating our finding of augmented mitochondrial metabolism upon VEN-resistance. Using oligomycin, an inhibitor of the complex V/ATPase subunit, we found synergistic activity and apoptosis induction in VEN-resistant BCP-ALL cell lines and PDX samples, demonstrating that acquired and intrinsic VEN-insensitivity can be overcome by co-targeting BCL-2 and the OxPhos pathway. These findings of reprogrammed, high mitochondrial metabolism in VEN-resistance and synergistic activity upon co-targeting BCL-2 and oxidative phosphorylation, strongly suggest further preclinical and potential clinical evaluation in VEN-resistant BCP-ALL.

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

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