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Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia

Dafflon, Caroline and Craig, Vanessa and Mereau, Helene and Gräsel, Julius and Schacher Engstler, Barbara and Hoffman, Gregory and Nigsch, Florian and Gaulis, Swann and Barys, Louise and Ito, Moriko and Aguadé Gorgorio, Julia and Bornhauser, Beat and Bourquin, Jean-Pierre and Proske, Amelie and Stork-Fux, Caroline and Murakami, Masato and Sellers, William and Hofmann, Francesco and Schwaller, Jürg and Tiedt, Ralph (2017) Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia. Leukemia. ISSN 14765551

Abstract

Chromosomal rearrangements of the mixed lineage leukemia (MLL/KMT2A) gene leading to oncogenic MLL-fusion proteins occur in ~10% of acute leukemias and are associated with poor clinical outcomes, emphasizing the need for new treatment modalities. Inhibition of the DOT1-like histone H3K79 methyltransferase (DOT1L) is a specific therapeutic approach for such leukemias that is currently being tested in clinical trials. However, in most MLL-rearranged leukemia models responses to DOT1L inhibitors are limited. Here, we performed deep-coverage short hairpin RNA sensitizer screens in DOT1L inhibitor-treated MLL-rearranged leukemia cell lines and discovered that targeting additional nodes of MLL complexes concomitantly with DOT1L inhibition bears great potential for superior therapeutic results. Most notably, combination of a DOT1L inhibitor with an inhibitor of the MLL–Menin interaction markedly enhanced induction of differentiation and cell killing in various MLL disease models including primary leukemia cells, while sparing normal hematopoiesis and leukemias without MLL rearrangements. Gene expression analysis on human and murine leukemic cells revealed that target genes of MLL-fusion proteins and MYC were suppressed more profoundly upon combination treatment. Our findings provide a strong rationale for a novel targeted combination therapy that is expected to improve therapeutic outcomes in patients with MLL-rearranged leukemia.Leukemia advance online publication, 3 January 2017; doi:10.1038/leu.2016.327.

Item Type: Article
Date Deposited: 15 Mar 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/29125

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