KDM4 inhibition increases sensitivity to cytarabine in Setd2-mutant leukemia cells. (A) MOLM-13 isogenic control 3 or SETD2 clone 1 were treated with JIB-04 or DMSO and western blotted for H3K36me3. (B) MLL-AF9 Setd2^+/+ or Setd2^fl/+ Mx1-cre cells were treated with JIB-04 or DMSO and western blotted for H3K36me3. (C) Cell titer Glo was used to determine the percentage of cell viability after 72 hours of JIB-04 for MOLM-13 isogenic control 3 or SETD2 clone 1. (D) Cell titer Glo was used to determine the percentage of cell viability after 72 hours of cytarabine for MOLM-13 isogenic control 3 or SETD2 clone 1, with or without JIB-04 (10 nM). (E) Mice with secondary MLL-AF9 Setd2fl^/+ Mx1-cre leukemia received a single dose of vehicle (n = 4), cytarabine (n = 5), JIB-04 (n = 5), and cytarabine with JIB-04 (n = 6) when their PB GFP was ∼40% and were rebled 12 to 16 hours later to determine the reduction in cell number, expressed as a percentage of pretreatment GFP, or (F) stained with AnnexinV to determine the amount of apoptosis after treatment.