A microRNA expression signature in infant t(4;11) MLL-AF4+ BCP-ALL uncovers novel therapeutic targets

Infants and children with MLL-AF4+ leukemia have an urgent need for more efficient and less aggressive therapy. In this study, we studied three microRNAs that are downregulated in MLL-AF4+ B-cell precursor acute lymphoblastic leukemia (BCP-ALL): miR-194, miR-99b and miR-125a-5p. When overexpressed, all three microRNAs impaired the survival of MLL-AF4+ leukemic blasts and the maintenance of MLL-AF4+ BCP-ALL. We identified microRNA target genes responsible for this phenotype that are upregulated in MLL-AF4+ BCP-ALL: CA5B, PPP3CA and PPP2R5C. Using CRISPR-Cas9 and specific inhibitors, we confirmed that CA5B, PPP3CA and PPP2R5C downregulation/inhibition severely compromised the proliferation and survival of MLL-AF4+ leukemic blasts. Importantly, CA5B, PPP3CA and PP2A inhibition by acetazolamide, tacrolimus and LB-100, respectively, showed high toxicity towards MLL-AF4+ leukemic blasts and reduced leukemia burden in vivo. This study highlights how the unique microRNA expression signature of patients with MLL-AF4+ BCP-ALL can be used to uncover novel therapeutic avenues and accelerate drug repurposing. Statement of significanceThere is an urgent need to identify novel therapeutic avenues for patients with MLL-AF4+ BCP-ALL that are more effective and less aggressive. This study identified three clinically available drugs (acetazolamide, tacrolimus and LB-100) with high and selective toxicity towards MLL-AF4+ leukemic cells.