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Nat Methods. 2014 Apr;11(4):436-42. doi: 10.1038/nmeth.2847. Epub 2014 Feb 23.

Identification of small molecules that support human leukemia stem cell activity ex vivo.

Author information

  • 1Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
  • 21] Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada. [2] Chemistry Department, University of Montreal, Montreal, Quebec, Canada.
  • 31] 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.
  • 41] 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.

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.

PMID:
24562423
[PubMed - indexed for MEDLINE]
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