title: Identification of small molecules that support human leukemia stem cell activity ex vivo.
abstract: Leukemic stem cells (LSCs) are considered a major cause of relapse in acute myeloid leukemia (AML). Defining pathways that control LSC self-renewal is crucial for a better understanding of underlying mechanisms and for the development of targeted therapies. However, currently available culture conditions do not prevent spontaneous differentiation of LSCs, which greatly limits the feasibility of cell-based assays. To overcome these constraints we conducted a high-throughput chemical screen and identified small molecules that inhibit differentiation and support LSC activity in vitro. Similar to reports with cord blood stem cells, several of these compounds suppressed the aryl-hydrocarbon receptor (AhR) pathway, which we show to be inactive in vivo and rapidly activated ex vivo in AML cells. We also identified a compound, UM729, that collaborates with AhR suppressors in preventing AML cell differentiation. Together, these findings provide newly defined culture conditions for improved ex vivo culture of primary human AML cells.
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Pabst
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Jana
authors.initials: J
authors.lastname: Krosl
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Iman
authors.initials: I
authors.lastname: Fares
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Boucher
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Réjean
authors.initials: R
authors.lastname: Ruel
authors.affiliation: 1] Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada. [2] Chemistry Department, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Marinier
authors.affiliation: 1] Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada. [2] Department of Computer Science and Operations Research, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lemieux
authors.affiliation: 1] Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada. [2] Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada. [3] Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada. [4] Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Hébert
authors.affiliation: 1] Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada. [2] Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada. [3] Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada. [4] Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018929:Cell Culture Techniques / Q000379:methods*; D016895:Culture Media, Serum-Free; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007938:Leukemia / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute; D015394:Molecular Structure; D014411:Neoplastic Stem Cells / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D016895:Culture Media, Serum-Free; D007211:Indoles; D011743:Pyrimidines; C000588694:UM729 compound; D000225:Adenine