TY - JOUR T1 - A microRNA expression signature in infant t(4;11) KMT2A::AFF1+ BCP-ALL uncovers novel therapeutic targets. AU - Malouf,Camille, AU - Duguid,Alasdair, AU - Vrenken,Kirsten S, AU - Leah,Tom, AU - Medhi,Ragini, AU - Camiolo,Giuseppina, AU - Nitsche,Leslie, AU - Jakobczyk,Hélène, AU - Kotecha,Rishi S, AU - Anderson,Richard A, AU - Barrett,Neil A, AU - Smith,Owen P, AU - Stam,Ronald W, AU - Ottersbach,Katrin, Y1 - 2026/04/23/ PY - 2025/6/20/received PY - 2026/2/20/revised PY - 2026/3/4/accepted PY - 2026/4/27/medline PY - 2026/4/27/pubmed PY - 2026/4/27/entrez PY - 2026/4/23/pmc-release SP - e70353 EP - e70353 JF - HemaSphere JO - Hemasphere VL - 10 IS - 4 N2 - Infants and children with KMT2A::AFF1+ leukemia have a dismal prognosis and are therefore in urgent need for more efficient and less aggressive therapy. In this study, we investigated three microRNAs that are downregulated in KMT2A::AFF1+ 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 KMT2A::AFF1+ leukemic blasts and the maintenance of KMT2A::AFF1+ BCP-ALL. We identified microRNA target genes responsible for this phenotype that are upregulated in KMT2A::AFF1+ BCP-ALL: CA5B, PPP3CA, and PPP2R5C. Importantly, using a drug-repurposing approach, we found that inhibition of CA5B, PPP3CA, and PP2A by acetazolamide, tacrolimus, and LB-100, respectively, showed high toxicity toward KMT2A::AFF1+ leukemic blasts and reduced leukemia burden in vivo. Furthermore, acetazolamide was able to prolong the survival of patient-derived xenotransplant models in combination with infant ALL induction therapy. This study highlights how the unique microRNA expression signature of patients with KMT2A::AFF1+ BCP-ALL can be used to uncover novel therapeutic avenues and accelerate drug repurposing. It also indicates potential new drug combinations for less toxic chemotherapy. SN - 2572-9241 UR - https://www.unboundmedicine.com/prime/citation/42038742/A_microRNA_expression_signature_in_infant_t(4 DB - PRIME DP - Unbound Medicine ER -