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Repression of DNA Damage Response Sensitizes APL Cells to the Combined Genotoxicity of All-Trans Retinoic Acid and Arsenic Trioxide

ABSTRACT: The synergistic combination of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO) has transformed acute promyelocytic leukemia (APL) from a terminal disease into a curable one. However, the molecular basis for the APL-specific synergy remains to be fully defined. In this work, we studied the mechanism that drives the unique efficacy of ATRA/ATO on APL cells. We found that the ATRA/ATO combination generates a high level of endogenous genotoxic stress, leading to exacerbated accumulation of DNA damage in APL cellular models and patient samples. Crucially, we found that ATRA-treatment triggers the ubiquitin-proteasome -mediated degradation of key DNA damage response proteins, including ATM and FANCD2. This APL-specific event is independent of PML-RARA turnover and creates a profound vulnerability to genotoxic stress, rendering APL cells more susceptible to the combined genotoxic stress from the ATRA-ATO combination. Our findings reveal that the synergized induction of genotoxic stress and the concurrent impairment of the DNA damage response mechanisms constitute a lethal "Double-Hit" that promotes APL-specific apoptosis. This study provides a novel paradigm for understanding therapeutic synergy and suggests that targeting DDR protein stability may extend the success of differentiation therapy to a broader range of leukemia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330966 | GEO | 2026/05/16

REPOSITORIES: GEO

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Project description:Acute promyelocytic leukaemia (APL) can be cured by the co-administration of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA). These small molecules relieve the differentiation blockade of the cancerous promyelocytes and trigger their maturation into functional neutrophils, which are physiologically primed for apoptosis. This normalization therapy uses low dose treatments and represents a compelling alternative to cytotoxic anticancer chemotherapy. However, the serendipitous discovery of this combination treatment prevented the establishment of methodologies to screen for novel combination treatments consisting of inducers of differentiation and other metallopharmaceuticals. Here, we present an experimental framework that enables interrogating the suitability, directionality and extent of normalization of novel combination treatments. Since the endpoint of this anticancer treatment is remodelling of cancer phenotypes, this approach requires a mechanism-driven understanding of the drug-induced cellular adaptions along the path to mature neutrophils. For this purpose, label-free quantification proteomics is used to probe the proteome changes upon differentiation and metal(-loid) treatment on the molecular level in a panel of ATRA-responsive and ATRA-non-responsive acute myeloid leukaemia (AML) cell lines, including APL. The induction of differentiation was confirmed by the up-regulation of canonical surface markers (e.g. CD11β) and validated by flow cytometry. The regulation of key transcription factors in this panel of AML cell lines reflects their position in the myeloid differentiation cascade (e.g. SPI1, GFI-1 and CEBPE). The additive/synergistic contributions of ATO to the combination treatment were thoroughly characterized and include changes in metabolic activities, as well as protein signatures related to management of reactive oxygen species and an integrated stress response. The latter two are also characteristic for the organoruthenium-based drug candidate plecstatin-1, which was recently shown to modulate the scaffold protein plectin. The combination of differentiation-induction and plecstatin-1 treatment featured a striking similarity in the responsiveness of the AML cancer cells compared to ATO+ATRA. It turned out to be at least equivalent in the regulation of key processes underlying normalization therapy in AML with granulocytic maturation. By exploiting response patterns of AML cancer cells induced by the ATO+ATRA combination treatment, this approach may allow identifying novel small molecule combinations, which may have the potential to achieve normalization and thus therapeutic benefit beyond APL.

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Repression of DNA Damage Response Sensitizes APL Cells to the Combined Genotoxicity of All-Trans Retinoic Acid and Arsenic Trioxide

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