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Journal/Book: Leukemia
Published: 2023
Pages: 2367-2382
Volume: 37
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PDP1 is a key metabolic gatekeeper and modulator of drug resistance in FLT3-ITD-positive acute myeloid leukemia

Islam Alshamleh, Nina Kurrle, Philipp Markowka, Raj Bhayadia, Rahul Kumar, Sebastian Süsser, Marcel Seibert, Damian Ludig, Sebastian Wolf, Sebastian E. Koschade, Karoline Stoschek, Johanna Kreitz, Dominik C. Fuhmann, Rosa Toenges, MArco Notaro, Federico Comoglio, Jan Jacob Schuringa, Tobias Berg, Bernhard Brüne, Daniela S. Krause, Jan-Henning Klusmann, Thomas Oellerich, Frank Schütgen*, Harald Schwalbe*, Hubert Serve*
Abstract:
High metabolic flexibility is pivotal for the persistence and therapy resistance of acute myeloid leukemia (AML). In 20–30% of AMLpatients, 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 thetricarboxylic 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 inreduced 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 respiratorycapacity during reoxygenation. Moreover, we show that PDP1 modifies the response to FLT3 inhibition. Upon incubation with theFLT3 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 resistancein cell lines and peripheral blasts from an AC220-resistant AML patient in vivo. In conclusion, FLT3-ITD assures the expression ofPDP1, a pivotal metabolic regulator that enhances oxidative glucose metabolism and drug resistance. Hence, PDP1 emerges as apotentially targetable vulnerability in the management of AML.
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Prof. Dr. Harald Schwalbe
Institut für Organische Chemie und Chemische Biologie
Johann Wolfgang Goethe Universität
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