title: The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias.
abstract: Using next-generation sequencing of primary acute myeloid leukemia (AML) specimens, we identified to our knowledge the first unifying genetic network common to the two subgroups of KMT2A (MLL)-rearranged leukemia, namely having MLL fusions or partial tandem duplications. Within this network, we experimentally confirmed upregulation of the gene with the most subtype-specific increase in expression, LOC100289656, and identified cryptic MLL fusions, including a new MLL-ENAH fusion. We also identified a subset of MLL fusion specimens carrying mutations in SPI1 accompanied by inactivation of its transcriptional network, as well as frequent RAS pathway mutations, which sensitized the leukemias to synthetic lethal interactions between MEK and receptor tyrosine kinase inhibitors. This transcriptomics-based characterization and chemical interrogation of human MLL-rearranged AML was a valuable approach for identifying complementary features that define this disease.
authors.affiliation: The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.|Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
authors.forename: Vincent-Philippe
authors.initials: VP
authors.lastname: Lavallée
authors.affiliation: The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Irène
authors.initials: I
authors.lastname: Baccelli
authors.affiliation: The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jana
authors.initials: J
authors.lastname: Krosl
authors.affiliation: The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.|Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Wilhelm
authors.affiliation: The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.|Centre Hospitalier Universitaire de Québec, Centre de Recherche du Centre Hospitalier de l'Université Laval and Hôpital de l'Enfant-Jésus, Quebec City, Quebec, Canada.|Department of Medicine, Université Laval, Quebec City, Quebec, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Barabé
authors.affiliation: The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Gendron
authors.affiliation: The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Boucher
authors.affiliation: The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.|Department of Computer Science and Operations Research, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Sébastien
authors.identifier: http://orcid.org/0000-0001-5477-1386
authors.initials: S
authors.lastname: Lemieux
authors.affiliation: The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.|Department of Chemistry, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Marinier
authors.affiliation: Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada.|Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.affiliation: The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.|Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.|Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.|Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Hébert
authors.affiliation: The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.|Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.|Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.|Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016022:Case-Control Studies; D019008:Drug Resistance, Neoplasm; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D059467:Transcriptome; D014178:Translocation, Genetic; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C497422:KMT2A protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D018631:ras Proteins