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In this study, we investigated three microRNAs that are downregulated in KMT2A::AFF1+ B\u2010cell precursor acute lymphoblastic leukemia (BCP\u2010ALL): miR\u2010194, miR\u201099b, and miR\u2010125a\u20105p. When overexpressed, all three microRNAs impaired the survival of KMT2A::AFF1+ leukemic blasts and the maintenance of KMT2A::AFF1+ BCP\u2010ALL. We identified microRNA target genes responsible for this phenotype that are upregulated in KMT2A::AFF1+ BCP\u2010ALL: CA5B, PPP3CA, and PPP2R5C. Importantly, using a drug\u2010repurposing approach, we found that inhibition of CA5B, PPP3CA, and PP2A by acetazolamide, tacrolimus, and LB\u2010100, 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\u2010derived xenotransplant models in combination with infant ALL induction therapy. This study highlights how the unique microRNA expression signature of patients with KMT2A::AFF1+ BCP\u2010ALL can be used to uncover novel therapeutic avenues and accelerate drug repurposing. It also indicates potential new drug combinations for less toxic chemotherapy.<\/jats:p>","DOI":"10.1002\/hem3.70353","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T09:03:32Z","timestamp":1776935012000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A microRNA expression signature in infant t(4;11) KMT2A::AFF1+ BCP\u2010ALL uncovers novel therapeutic targets"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1066-8376","authenticated-orcid":false,"given":"Camille","family":"Malouf","sequence":"first","affiliation":[{"name":"Centre for Regenerative Medicine, Institute for Regeneration and Repair University of Edinburgh Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alasdair","family":"Duguid","sequence":"additional","affiliation":[{"name":"Centre for Regenerative Medicine, Institute for Regeneration and Repair 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