SRA

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) harboring both inv(3)/t(3;3) and monosomy 7 (-7) are highly aggressive myeloid cancers whose molecular pathogenesis and therapeutic vulnerability remain elusive. High throughput drug screens, CUT&Tag/RNA sequence and functional assays using human MDS/AML cells revealed that EZH2 inhibitors efficiently induce apoptosis preferentially in MDS/AML with inv(3)/t(3;3) and -7 through activation of GADD45?-p38-p53 axis. EVI1 activated in 3q-rearranged MDS/AML was responsible for GADD45? silencing by direct binding to its consensus sequence within GADD45? promoter and recruitment of PRC2 complex via interaction with EZH2, which can be therapeutically targeted by EZH2 inhibition. MDS/AML with inv(3)/t(3;3) and -7 showed preferential sensitivity to EZH2 inhibition in both mouse model and patient samples. Thus, MDS/AML cells with inv(3)/t(3;3) and -7 possess apoptosis evasion mechanism through EVI1-PRC2-mediated repression of GADD45?-p38-p53 axis, which is a potential therapeutic vulnerability in MDS/AML patients with these high-risk cytogenetic lesions. Overall design: To explore the downstream target of EZH2 inhibition relevant to apoptosis induction in YCU-AML1 and OCI-AML20 cells, we performed CUT&Tag sequence (CUT&Tag-seq) for H3K27me3 using OCI-AML20, YCU-AML1, FKH-1 and Kasumi-3 cells treated with either vehicle or valemetostat 300nM for 7 days.