1. Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia
- Author
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Florian Nigsch, Júlia Aguadé-Gorgorió, J Gräsel, H Méreau, B Schacher Engstler, Beat Bornhauser, Louise Barys, William R. Sellers, J-P Bourquin, Gregory R. Hoffman, C Stork-Fux, Ralph Tiedt, Caroline Dafflon, Francesco Hofmann, Juerg Schwaller, Swann Gaulis, A Proske, Masato Murakami, V J Craig, Moriko Ito, University of Zurich, and Dafflon, C
- Subjects
0301 basic medicine ,Cancer Research ,2720 Hematology ,Mice, Nude ,Apoptosis ,610 Medicine & health ,Small hairpin RNA ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,1306 Cancer Research ,Enzyme Inhibitors ,RNA, Small Interfering ,neoplasms ,Cell Proliferation ,Gene Rearrangement ,Regulation of gene expression ,Leukemia ,biology ,Gene Expression Regulation, Leukemic ,Histone-Lysine N-Methyltransferase ,Methyltransferases ,Hematology ,Gene rearrangement ,DOT1L ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,KMT2A ,Histone ,Cell killing ,Oncology ,Drug Resistance, Neoplasm ,10036 Medical Clinic ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,2730 Oncology ,Myeloid-Lymphoid Leukemia Protein - 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.
- Published
- 2016