Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by poor clinical outcomes and high relapse rates, driven largely by intrinsic or acquired chemoresistance. Despite advances, the standard "7 + 3″ chemotherapy backbone offers limited long-term survival, underscoring the urgent need for novel molecular targets to overcome therapeutic bottlenecks. While the AP-1 transcription factor FOSL2 is implicated in solid tumors, its role in AML remains unexplored. Here, we identify and validate FOSL2 as a critical oncogenic driver in AML. Comprehensive bioinformatic analysis across multiple independent patient cohorts reveals that its aberrant overexpression is a key feature and robust biomarker, correlating significantly with adverse clinical outcomes. Functional studies using shRNA-mediated silencing demonstrated that FOSL2 is indispensable for leukemic cell survival and proliferation. Its genetic depletion profoundly abrogated clonogenic potential, induced G0/G1 cell-cycle arrest and apoptosis, and promoted myeloid differentiation in vitro. In a xenograft mouse model, FOSL2 knockdown markedly suppressed leukemic tumor burden and significantly extended overall survival. Mechanistically, transcriptomic profiling revealed that FOSL2 depletion upregulates the E3 ubiquitin ligase HRD1 suggesting that FOSL2 depletion may hyperactivate the endoplasmic reticulum-associated degradation (ERAD) pathway. This uncontrolled ERAD activity dismantles cellular proteostasis, culminating in heightened ER stress and significant DNA damage, as evidenced by comet assays. Consequently, this FOSL2-deficient state profoundly sensitizes AML cells to conventional chemotherapies, including doxorubicin and cytarabine, as well as ER stress-inducing agents. Collectively, these findings establish that FOSL2 orchestrates a key proteostatic vulnerability. Targeting the FOSL2-ERAD axis represents a compelling therapeutic strategy to dismantle chemoresistance and improve patien