Disruption of the menin–MLL interaction inhibits MLL leukemia without affecting normal hematopoiesis.

  • Major finding: Disruption of the menin–MLL interaction inhibits MLL leukemia without affecting normal hematopoiesis.

  • Concept: Menin is a required cofactor for MLL fusion protein–driven leukemic transformation.

  • Impact: Small-molecule inhibition of menin–MLL may be a viable therapeutic approach for acute MLL leukemias.

Chromosomal translocations of the mixed-lineage leukemia (MLL) gene frequently occur in aggressive acute leukemias affecting both children and adults. All MLL fusion proteins retain the N-terminal fragment of MLL that binds menin, a necessary cofactor for MLL fusion protein–induced oncogenic transformation, but not normal hematopoiesis. Genetic deletion of Men1 (which encodes menin) suppresses acute leukemia development, suggesting that the menin–MLL interaction may be an attractive therapeutic target. Borkin, He, Miao, and colleagues developed two small-molecule inhibitors that bound menin with low nanomolar affinity, potently blocked the menin–MLL interaction, and exhibited favorable pharmacokinetic profiles. These pharmacologic inhibitors showed selective, on-target activity in MLL leukemia cells, but not leukemia cells lacking MLL translocations, resulting in growth suppression and induction of differentiation in vitro. Analysis of global gene expression profiles showed that inhibitor treatment downregulated MLL target genes implicated in leukemogenesis, such as homeobox genes, and upregulated genes associated with myeloid differentiation. Furthermore, single-agent treatment with menin–MLL inhibitors significantly reduced tumor volume, delayed leukemia progression, and increased survival in both xenograft and xenotransplantation mouse models of MLL leukemia. Consistent with these findings, menin–MLL inhibitors reduced the clonogenic growth of patient-derived MLL leukemia samples, but had little effect on primary acute myelogenous leukemia patient samples without MLL translocations. Importantly, prolonged administration of menin–MLL inhibitors did not induce toxicity or impair normal hematopoiesis in vivo, supporting a therapeutic window for these compounds. Together, these studies highlight small-molecule inhibition of the menin–MLL interaction as a viable therapeutic approach for acute MLL-rearranged leukemia and support further optimization to identify clinical lead compounds.

Borkin D, He S, Miao H, Kempinska K, Pollock J, Chase J, et al. Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell 2015 Mar 26 [Epub ahead of print].

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