Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Abstract

Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of PML nuclear bodies (NBs), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mtDNA, activating cGAS signaling and boosting ROS production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies. SIGNIFICANCEActinomycin D induces complete remissions in NPM1-mutant AMLs. We found that NPM1c affects mitochondrial biogenesis and PML bodies (NBs).Actinomycin D targets mitochondria, yielding ROS which enforce PML NB-biogenesis and restore senescence. Dual targeting of mitochondria with actinomycin D and venetoclax sharply potentiates their anti-AML activities in vivo.Research.

Mitochondrial Contributions to Hematopoietic Stem Cell Aging

“…AML is an aggressive hematological disorder mainly affecting people of advancing age, and 30% of patients with AML are 75 years or older [168]. Notably, we recently revealed a mitochondrial ROS senescence pathway triggered by Nucleophosmin 1 mutant (NPM1c), PML, and TP53, which plays a crucial role in actinomycin D-based therapies in AML [169]. This supports the idea of mitochondria as potential therapeutic target.…”

EAPB0503, an Imidazoquinoxaline Derivative Modulates SENP3/ARF Mediated SUMOylation, and Induces NPM1c Degradation in NPM1 Mutant AML

“…Likewise, Actinomycin D induced complete remissions in NPM1c AMLs [ 28 , 48 , 49 ], and this clinical efficacy happened via targeting mitochondria, boosting reactive oxygen species production, hence restoring senescence of NPM1c expressing cells. Dual targeting of mitochondria with actinomycin D and the BCL-2 inhibitor venetoclax sharply potentiated the in vivo anti-AML activities of these drugs [ 27 ]. Venetoclax alone, or combined to low intensity chemotherapy, Arsenic or menin inhibitors proved efficient in preclinical and more importantly in different categories of NPM1c AML patients including those with minimal residual disease, or relapsed refractory patients [ 29 , 30 , 50 , 51 , 52 , 53 ].…”

“…Complete remission is achieved in almost 70% of treated patients; however, relapse represents the major cause of treatment failure [ 24 ]. Currently, the clinical management of AML started shifting towards incorporating targeted therapies against key driving mutations [ 10 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Many of these targeted therapies are still under pre-clinical or clinical investigation [ 32 , 33 , 34 ].…”

The Elephant in The Room: AML Relapse Post Allogeneic Hematopoietic Cell Transplantation

“…A recently reported study combined actinomycin D, with azacitidine and venetoclax for the treatment of AML relapse post allo-HCT. The rationale of adding actinomycin D was based on preclinical data suggesting a synergistic anti-leukemic effect through MCL1 degradation, in addition to mitochondrial activity yielding to senescence through PML-nuclear body biogenesis (41)(42)(43). Twenty patients were treated with the triplet combination with an impressive ORR of 75% and a median OS of 13.1 months (41).…”