title: Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Dafflon
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: V J
authors.initials: VJ
authors.lastname: Craig
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Méreau
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Gräsel
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Schacher Engstler
authors.affiliation: Novartis Institutes for BioMedical Research, Developmental and Molecular Pathways, Cambridge, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Hoffman
authors.affiliation: Novartis Institutes for BioMedical Research, Developmental and Molecular Pathways, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Nigsch
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Gaulis
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Barys
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Aguadé-Gorgorió
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Bornhauser
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: J-P
authors.initials: JP
authors.lastname: Bourquin
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Proske
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Stork-Fux
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Cambridge, MA, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: Sellers
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Schwaller
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Tiedt
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; C497422:KMT2A protein, human; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D051788:Myeloid-Lymphoid Leukemia Protein; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase