Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with MLL rearrangement or NPM1 mutation to venetoclax

Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with MLL rearrangement or NPM1 mutation to venetoclaxAcute myeloid leukemia (AML) represents a genetically heterogeneous group of myeloid neoplasms derived from early hematopoietic progenitors.Mutations in the NPM1 gene and chromosomal rearrangements of the gene encoding the histone 3 lysine 4 (H3K4) methyltransferase MLL (KMT2A) represent recurrent genetic abnormalities that define distinct AML subtypes and predict treatment outcomes. 1,2Both genetic alterations in AML are associated with activating a particular leukemogenic transcriptional program, including the aberrant expression of the self-renewal associated homeobox (HOX), MEIS1, and PBX3 transcription factor genes and their target genes FLT3 and BCL2. 3 The interaction of MLL with the adaptor protein menin is required for MLL-rearranged (MLL-r) leukemogenesis, 3 and we discovered that NPM1 mut AML also depends on the menin binding motif in MLL. 4 Small-molecule inhibitors that block the menin-MLL interaction cause downregulation of leukemic gene expression, induce differentiation, and have anti-leukemic ac-tivity against NPM1 mut and MLL-r leukemia models (reviewed in 5 ).Ziftomenib is one of five menin inhibitors currently assessed in clinical phase I/II trials (clinicaltrials gov.Identifiers: NCT04067336, NCT04065399, NCT05153330, NCT04811560, NCT04988555) with explorative single-agent efficacy of ziftomenib reported in relapsed or refractory AML.Here, we selectively screened for synergistic treatment partners using a combinatorial drug screen and deciphered synergistic effects of ziftomenib on MLL-r and NPM1 mut AML.In order to characterize the single-drug treatment effects of ziftomenib, we first assessed its anti-proliferative activity in various MLL-r (MOLM13, MV411, OCI-AML2) and NPM1 mut (OCI-AML3) human AML cell lines.Similar to other menin inhibitors such as VTP-50469, we observed strong and dose-dependent inhibitory effects in all MLL-r and NPM1 mut AML at low nanomolar concentrations upon 7 days of treatment (half-maximal inhibitory concentration IC 50 <25 nM; Figure 1A,B).HL60 and NB4 AML cells with-C