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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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Project description:Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of functions including ribosome biogenesis, mRNA processing, and maintenance of genomic stability1-4. In acute myeloid leukemia (AML), the terminal exon of NPM1 is often mutated (~30% of adult AMLs), resulting in the change of the nucleolar localization signal into a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c)2,3,5. AMLs carrying this mutation have aberrant expression of the HOXA genes, whose overexpression leads to leukemogenic transformation6-8. Recently, it was shown that depletion or re-localization of the NPM1c protein into the nucleus causes downregulation of the HOXA genes, leading to the speculation that NPM1c directly regulates their transcription9-11. Here, we show that NPM1c binds to a subset of active gene promoters marked with high levels of H3K27ac in NPM1c leukemia cell lines and primary leukemia blasts, including well-known leukemia-driving genes such as posterior HOXA, HOXB, and MEIS1/PBX3 genes as well as novel targets IRX5 and NKX2-3. The binding of NPM1c on chromatin sustains active transcription of key target genes by maintaining high local-concentration of transcriptional complexes, including the Super Elongation Complex (SEC) and Menin/MLL1. NPM1c also maintains the active chromatin landscape by inhibiting the activity of histone deacetylases (HDACs). Depletion of NPM1c causes histone deacetylation and the silencing of key leukemic genes, leading to cell differentiation and growth arrest. The export protein XPO1 plays a key role by tethering NPM1c onto chromatin. The combination of XPO1 inhibitors (e.g., Selinexor and Eltanexor) with the Menin inhibitor MI-3454 has a synergistic effect on inducing differentiation in both NPM1-mutated leukemia cell lines and PDX model. Together, these findings reveal the neomorphic function of NPM1c as transactivator for leukemic gene expression and open up potential avenues for therapeutic intervention.

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Actinomycin targets NPM1c-primed mitochondria in AML

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