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Actinomycin targets NPM1c-primed mitochondria in AML

ABSTRACT: Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and association with favorable outcome remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) hampers formation of PML nuclear bodies (NBs), key senescence effectors, and impairs mitochondrial function to drive an integrated stress response. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, preferentially targets these primed mitochondria, activating cGAS signaling and boosting ROS production. The later restores PML NB formation to drive senescence of NPM1c-AMLs cells. Dual targeting of mitochondria by Venetoclax and ActD synergized for AML elimination. Our studies reveal a central role of mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as a key effector of ActD-based, and possibly others, chemotherapies.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Bone Marrow

DISEASE(S): Acute Myeloid Leukemia

SUBMITTER: François GUILLONNEAU

LAB HEAD: Hugues de Thé

PROVIDER: PXD025507 | Pride | 2021-12-17

REPOSITORIES: Pride

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			Action	DRS
	HuDT171219_AML2_NPM1_1_SCX1_Q24497.raw	Raw
	HuDT171219_AML2_NPM1_1_SCX2_Q24498.raw	Raw
	HuDT171219_AML2_NPM1_1_SCX3_Q24499.raw	Raw
	HuDT171219_AML2_NPM1_1_SCX4_Q24500.raw	Raw
	HuDT171219_AML2_NPM1_1_SCX5_Q24501.raw	Raw

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