ArticleLeukemia2023
PDP1 is a key metabolic gatekeeper and modulator of drug resistance in FLT3-ITD-positive acute myeloid leukemia.
Article in Leukemia, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 14 citations in OpenAlex.
- Quizartinib and omacetaxine mepesuccinate combination therapy in FLT3-ITD AML: a phase II trial.Nature communications · 2026Trial
- Immune Checkpoints in Leukaemia as Gatekeepers of Immuno-Modulation.Immunology · 2026Review
- Article
- Mitochondrial Dysfunction in Apoptosis-Resistant Acute Myeloid Leukemia Cells During a Sterile Inflammatory Response.Biomolecules · 2025Article
- Metabolic Signature ofJournal of personalized medicine · 2025Review
- Lactate-related gene signatures predict prognosis and immune profiles in esophageal squamous cell carcinoma.Scientific reports · 2025Article
- In silico development and validation of a novel six-gene-derived signature in hepatocellular carcinoma.Translational cancer research · 2025Article
- Article
- Protein serine/threonine phosphatases in tumor microenvironment: a vital player and a promising therapeutic target.Theranostics · 2025Review
- Emerging roles of pyruvate dehydrogenase phosphatase 1: a key player in metabolic health.Frontiers in physiology · 2025Review
- Mitochondrial pyruvate dehydrogenase phosphatase metabolism disorder in malignant tumors.Oncology research · 2025Review
- Mapping Natural Sugars Metabolism in Acute Myeloid Leukaemia Using 2D Nuclear Magnetic Resonance Spectroscopy.Cancers · 2024Article
- Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.Frontiers in oncology · 2024Review
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Authors and funding
25 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
High metabolic flexibility is pivotal for the persistence and therapy resistance of acute myeloid leukemia (AML). In 20-30% of AML patients, activating mutations of FLT3, specifically FLT3-ITD, are key therapeutic targets. Here, we investigated the influence of FLT3-ITD on AML metabolism. Nuclear Magnetic Resonance (NMR) profiling showed enhanced reshuffling of pyruvate towards the tricarboxylic acid (TCA) cycle, suggesting an increased activity of the pyruvate dehydrogenase complex (PDC). Consistently, FLT3-ITD-positive cells expressed high levels of PDP1, an activator of the PDC. Combining endogenous tagging of PDP1 with genome-wide CRISPR screens revealed that FLT3-ITD induces PDP1 expression through the RAS signaling axis. PDP1 knockdown resulted in reduced cellular respiration thereby impairing the proliferation of only FLT3-ITD cells. These cells continued to depend on PDP1, even in hypoxic conditions, and unlike FLT3-ITD-negative cells, they exhibited a rapid, PDP1-dependent revival of their respiratory capacity during reoxygenation. Moreover, we show that PDP1 modifies the response to FLT3 inhibition. Upon incubation with the FLT3 tyrosine kinase inhibitor quizartinib (AC220), PDP1 persisted or was upregulated, resulting in a further shift of glucose/pyruvate metabolism towards the TCA cycle. Overexpression of PDP1 enhanced, while PDP1 depletion diminished AC220 resistance in cell lines and peripheral blasts from an AC220-resistant AML patient in vivo. In conclusion, FLT3-ITD assures the expression of PDP1, a pivotal metabolic regulator that enhances oxidative glucose metabolism and drug resistance. Hence, PDP1 emerges as a potentially targetable vulnerability in the management of AML.
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