PMID- 24562423
OWN - NLM
STAT- MEDLINE
DCOM- 20140603
LR  - 20211021
IS  - 1548-7105 (Electronic)
IS  - 1548-7091 (Linking)
VI  - 11
IP  - 4
DP  - 2014 Apr
TI  - Identification of small molecules that support human leukemia stem cell activity 
      ex vivo.
PG  - 436-42
LID - 10.1038/nmeth.2847 [doi]
AB  - 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.
FAU - Pabst, Caroline
AU  - Pabst C
AD  - Institute for Research in Immunology and Cancer, University of Montreal, 
      Montreal, Quebec, Canada.
FAU - Krosl, Jana
AU  - Krosl J
AD  - Institute for Research in Immunology and Cancer, University of Montreal, 
      Montreal, Quebec, Canada.
FAU - Fares, Iman
AU  - Fares I
AD  - Institute for Research in Immunology and Cancer, University of Montreal, 
      Montreal, Quebec, Canada.
FAU - Boucher, Genevieve
AU  - Boucher G
AD  - Institute for Research in Immunology and Cancer, University of Montreal, 
      Montreal, Quebec, Canada.
FAU - Ruel, Rejean
AU  - Ruel R
AD  - Institute for Research in Immunology and Cancer, University of Montreal, 
      Montreal, Quebec, Canada.
FAU - Marinier, Anne
AU  - Marinier A
AD  - 1] Institute for Research in Immunology and Cancer, University of Montreal, 
      Montreal, Quebec, Canada. [2] Chemistry Department, University of Montreal, 
      Montreal, Quebec, Canada.
FAU - Lemieux, Sebastien
AU  - Lemieux S
AD  - 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.
FAU - Hebert, Josee
AU  - Hebert J
AD  - 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.
FAU - Sauvageau, Guy
AU  - Sauvageau G
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140223
PL  - United States
TA  - Nat Methods
JT  - Nature methods
JID - 101215604
RN  - 0 (Culture Media, Serum-Free)
RN  - 0 (Indoles)
RN  - 0 (Pyrimidines)
RN  - 0 (UM729 compound)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - Adenine/*analogs & derivatives/pharmacology
MH  - Cell Culture Techniques/*methods
MH  - Culture Media, Serum-Free
MH  - Drug Screening Assays, Antitumor
MH  - Humans
MH  - Indoles/*pharmacology
MH  - Leukemia/*metabolism
MH  - Leukemia, Myeloid, Acute
MH  - Molecular Structure
MH  - Neoplastic Stem Cells/*physiology
MH  - Pyrimidines/*pharmacology
EDAT- 2014/02/25 06:00
MHDA- 2014/06/04 06:00
CRDT- 2014/02/25 06:00
PHST- 2013/09/04 00:00 [received]
PHST- 2014/01/12 00:00 [accepted]
PHST- 2014/02/25 06:00 [entrez]
PHST- 2014/02/25 06:00 [pubmed]
PHST- 2014/06/04 06:00 [medline]
AID - nmeth.2847 [pii]
AID - 10.1038/nmeth.2847 [doi]
PST - ppublish
SO  - Nat Methods. 2014 Apr;11(4):436-42. doi: 10.1038/nmeth.2847. Epub 2014 Feb 23.