The MLL-Menin Interaction is a Therapeutic Vulnerability in NUP98 -rearranged AML.

Chromosomal translocations involving the locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with fusions is characterized by high expression of and genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin-MLL interaction inhibits the propagation of -rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as and . In addition, Menin inhibition reduces the expression of both wild-type and mutated -ITD, and in combination with FLT3 inhibitor, suppresses patient-derived -r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that -rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring fusions into the clinical evaluation of Menin inhibitors.