A novel metabolic role of Musashi-2 underlies glucocorticoid resistance in Acute Lymphoblastic Leukemia

The RNA-binding protein Musashi-2 (MSI2) is emerging as key regulator of cancer biology. However, its functional role in high-risk pediatric B-cell Acute Lymphoblastic Leukemia (B-ALL) is not fully elucidated. In this study, we demonstrate that MSI2 promotes leukemic cell growth in vitro and sustains the leukemogenic potential of KMT2A-rearranged infant ALL in vivo. Mechanistically, MSI2 is involved in Glucocorticoids resistance by regulating mitochondria metabolism. Targeting MSI2 impairs the mitochondrial function in leukemic cells upon Glucocorticoids exposure and increases their susceptibility to metabolic perturbations, highlighting a novel role of MSI2 in cell metabolism. Targeting the mitochondria activity in KMT2Ar infant ALL cells with OxPhos inhibitors may therefore represent a promising strategy to improve treatment response in patients. Overall, our findings identify MSI2 as a critical regulator of leukemic maintenance and drug resistance in KMT2Ar infant ALL, providing mechanistic insight into therapy failure and supporting the targeting of metabolic vulnerabilities as a promising therapeutic strategy for this high-risk pediatric leukemia.