Abstract 2497

Chromosomal translocations that affect the MLL (Mixed Lineage Leukemia) proto-oncogene occur in aggressive acute leukemias, both in children and adults. Fusion of MLL to one of more than 50 partner genes results in generation of the MLL fusion oncoprotein, which upregulates expression of HOX genes required for normal hematopoiesis, and ultimately leads to the development of acute leukemia. Patients harboring translocations of MLL gene suffer from very aggressive leukemias and respond poorly to available therapies, emphasizing the urgent need for novel therapeutic treatments. All oncogenic MLL fusion proteins have a preserved N-terminal fragment of MLL that interacts with menin, a tumor suppressor protein encoded by MEN1 (Multiple Endocrine Neoplasia 1) gene. Importantly, the menin-MLL fusion protein interaction is critical to the leukemogenic activity of MLL fusion proteins and misregulation of HOXA9 genes, and therefore it represents a valuable molecular target for therapeutic intervention. Selective targeting of the protein-protein interaction between menin and MLL fusion proteins with small molecules could block the oncogenic activity of MLL fusion proteins and inhibit development of acute leukemia.

To identify small molecule inhibitors of the menin-MLL interaction we have performed a High Throughput Screen of 350,000 compounds using a collection of biochemical assays and biophysical methods. This resulted in several classes of compounds that specifically bind to menin and inhibit the menin-MLL interaction both in vitro and in human cells. We then applied medicinal chemistry approaches to develop analogues of selected lead candidates, resulting in very potent compounds that inhibit the menin-MLL interaction with nanomolar affinities. To evaluate potency, specificity and mechanism of action of these compounds we used a broad collection of cellular assays. These compounds selectively inhibit proliferation of the MLL leukemia cells, strongly induce apoptosis and differentiation of these cells. Importantly, these compounds substantially downregulate expression of HOXA9 and MEIS1 genes that are downstream targets of MLL fusion proteins required for their leukemogenicity, and they also deplete the menin-MLL fusion protein complex from the target genes. Furthermore, the compounds that we developed specifically inhibit the MLL fusion protein mediated oncogenic transformation. All these effects closely recapitulate the effects observed upon acute loss of menin or disruption of the menin-MLL fusion protein interaction using genetic manipulations, demonstrating highly specific mode of action for these compounds. Our current efforts are focused to assess the effect of these compounds in in vivo models of MLL leukemia and evaluate their utility as future drug candidates for acute leukemias. This may provide a novel therapeutic approach for the treatment of very aggressive leukemias with MLL translocations.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.