title: A novel approach for the identification of efficient combination therapies in primary human acute myeloid leukemia specimens.
abstract: Appropriate culture methods for the interrogation of primary leukemic samples were hitherto lacking and current assays for compound screening are not adapted for large-scale investigation of synergistic combinations. In this study, we report a novel approach that efficiently distills synthetic lethal interactions between small molecules active on primary human acute myeloid leukemia (AML) specimens. In single-dose experiments and under culture conditions preserving leukemia stem cell activity, our strategy considerably reduces the number of tests needed for the identification of promising compound combinations. Initially conducted with a selected library of 5000 small molecules and 20 primary AML specimens, it reveals 5 broad classes of sensitized therapeutic target pathways along with their synergistic patient-specific fingerprints. This novel method opens new avenues for the development of AML personalized therapeutics and may be generalized to other tumor types, for which in vitro cancer stem cell cultures have been developed.
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Baccelli
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Krosl
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.
authors.forename: G
authors.identifier: 0000-0001-6389-9007
authors.initials: G
authors.lastname: Boucher
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Boivin
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.|Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.
authors.forename: V-P
authors.initials: VP
authors.lastname: Lavallée
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.|Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.|Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.|Faculty of Medicine, Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Hébert
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.|Department of Computer Science and Operations Research, Université de Montréal, Montréal, Québec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Lemieux
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.|Department of Chemistry, Université de Montréal, Montréal, Québec, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Marinier
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.|Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.|Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.|Faculty of Medicine, Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Sauvageau
mesh_terms: D003131:Combined Modality Therapy / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured