We evaluated the combination of RAS/MAPK pathway inhibition by the MEK1/2 inhibitor selumetinib with the Menin inhibitor VTP-50469 (SNDX-5613) in a genetically defined, poor prognostic subgroup of pediatric leukemia harboring KMT2A-r with RAS mutations….The combinatorial effect was also associated with an impairment of colony forming potential, decrease in cell growth with a G0/G1 arrest and promotion of cell death...We observed synergy with Menin and MEK inhibitors in a panel of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines and PDX models with KMT2A-r and RAS mutations...After 18 to 28 days of treatment, leukemia burden in bone marrow, spleen and peripheral blood was markedly decreased with the combination compared to the single drug-treated cohorts...