LAUSR

Acute myeloid leukemia (AML) is an aggressive blood cancer with limited therapeutic options against leukemic stem cells (LSCs), resulting in poor clinical outcomes for decades. We have demonstrated the clinical importance of aberrant activation of RSPO3/β-catenin pathway in a subset of poor prognosis AML (Cancer Cell, 38:263-278, 2020) and its ability to sustain low levels of reactive oxygen species (ROS), a critical characteristic of human LSCs. This current study has extended our recent finding, and for the first time linked the pathway activation to ferroptosis resistance, a new drug resistance mechanism in cancer therapy. Our single-cell multiomics data in patient-derived xenograft mouse models of relapsed AML showed that the pathway activation in human LSCs led to upregulation of 43 differentially expressed genes associated with iron detoxification (e.g., FTH1) and ROS sensing/detoxification (e.g., PRDX1), two key features of ferroptosis resistance. Consistent with this observation, we found that AML patient specimens with favourable outcomes, which are independent of RSPO3 pathway, were sensitive to RSL3 treatment leading to increased cell death associated with elevated levels of intracellular ROS and iron. In contrast, AML patient specimens with poor clinical outcomes, which critically depend on RSPO3 pathway activation for survival and maintenance of myeloid undifferentiated state, revealed resistance to ferroptosis inducers (e.g., RSL3). Intriguingly, we found that anti-RSPO3 antibody, a clinical-grade drug that inhibits AML LSCs by blocking the interaction of RSPO3 with its receptor, sensitizes human LSCs to RSL3 treatment, leading to reduced cell viability. Overall, this study is the first to demonstrate the role of ferroptosis resistance in human LSCs and provides an opportunity to develop precision combination therapy by concurrently targeting self-renewal and ferroptosis resistance to improve therapeutic outcomes for patients with poor-risk AML. Citation Format: Nunki Hassan, Hangyu Yi, Lucie Gaspard-Boulinc, Jenny Wang. Leukemic stem cells confer ferroptosis resistance in aggressive blood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5795.