Furthermore, we demonstrate that upon DYRK1A inhibition, the expression levels of the antiapoptotic factor BCL-XL are reduced, which consequently renders KMT2A-R ALL cells sensitive to dual DYRK1A and venetoclax inhibition and significantly extends the survival of mice transplanted with KMT2A-R ALL, indicating that a DYRK1A inhibitor-based therapy is a novel approach for the treatment of KMT2A-R ALL. Here, BCL2L1 is linked to acute lymphoblastic leukemia.