3031 – MSI2 PLAYS A ROLE IN GLUCOCORTICOIDS RESISTANCE OF MLL-REARRANGED ALL BY REGULATING THE ENERGY METABOLISM OF LEUKEMIC CELLS

Musashi-2 (MSI2) is an RNA-binding protein involved in the post-transcriptional regulation of specific mRNA targets. It has a crucial role in proliferation, differentiation and maintenance of stem cell pool both in normal and malignant hematopoiesis, including myeloid leukemias. However, the functional role of MSI2 in Acute Lymphoblastic Leukemia (ALL) is still unknown. Herein we specifically focused on MLL-rearranged (MLLr) ALL, a very aggressive disease occurring in infants (< 12 months), typically associated with resistance to current therapies, high-risk of relapse and overall poor outcome. At present, the identification of potentially targetable genes involved in the pathogenesis of the disease is extremely urgent for the development of novel therapeutic approaches.By applying the CRISPR/CAS9 genome editing to the MLL-AF4+ ALL cell line SEM, we generated the SEM MSI2 KO cells. In a long-term competitive assay in vitro we observed that the lack of MSI2 affects the growth of MLL-AF4+ ALL cells. Also, SEM MSI2 KO cells have an impaired in vivo leukemia-initiating capacity in mice. Notably, we found that MSI2 KO cells were (100-fold) more sensitive to Glucocorticoids (GCs) compared to controls. Interestingly, by further investigating the mechanisms of GC-resistance/sensitization, we found that MSI2 KO cells have a defective energy metabolism upon GCs exposure, specifically involving ATP production via mitochondrial respiration. Finally, by treating the SEM cell line with the MSI2 inhibitor Ro 08-2750 we observed a synergistic effect in combination with GCs, and that the pharmacological inhibition of MSI2 affects the mitochondrial respiration.In conclusion, our study suggests that MSI2 has a crucial role in MLL-AF4+ ALL, by sustaining the cell proliferation, the in vivo leukemogenic potential, the GC-resistance and the metabolic plasticity/adaptation to stress.