Cell-state-dependent responses to PLK1 inhibition reveal a non-canonical microtubule-endolysosomal vulnerability in quiescent leukemia stem cells

PLK1 inhibition eradicates quiescent leukemia stem cells in acute myeloid leukemia by triggering apoptosis through disrupted vesicle trafficking and endolysosomal homeostasis, not mitotic arrest.

• Why it matters: Relapse in AML is often driven by therapy-resistant quiescent LSCs, and PLK1 inhibitors have been pursued mainly for antiproliferative effects that may not address this state.
• What they did: The study compared proliferating AML cells versus quiescence-enriched LSCs under PLK1 inhibition, using assays that tested mitotic arrest, apoptosis, vesicle trafficking, and an identified PLK1–MAP1A interaction.
• The result: Quiescent LSC apoptosis occurred independently of mitotic arrest, and combinatorial perturbations plus ex vivo and in vivo assays showed depletion of functionally defined LSCs, linking survival to microtubule regulation and endolysosomal homeostasis.

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