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

Abstract

Chromosomal translocations involving the <i>NUP98</i> locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with <i>NUP98</i> fusions is characterized by high expression of <i>HOXA</i> and <i>MEIS1</i> 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 <i>NUP98</i>-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 <i>MEIS1</i> and <i>CDK6</i>. In addition, Menin inhibition reduces the expression of both wild-type <i>FLT3</i> and mutated <i>FLT3</i>-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived <i>NUP98</i>-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 <i>NUP98</i>-rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring <i>NUP98</i> fusions into the clinical evaluation of Menin inhibitors.