GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE330nnn/GSE330966/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE330966GEOGSEfalseRepression of DNA Damage Response Sensitizes APL Cells to the Combined Genotoxicity of All-Trans Retinoic Acid and Arsenic TrioxideThe 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.2026/05/16GSE330966GSM9736650GSM9736639GSM9736648GSM9736637GSM9736649GSM9736638GSM9736646GSM9736635GSM9736647GSM9736636GSM9736644GSM9736633GSM9736645GSM9736634GSM9736642GSM9736631GSM9736653GSM9736654GSM9736643GSM9736632GSM9736651GSM9736640GSM9736652GSM973664134284330966Homo sapiens