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Blood, 5 November 2009, Vol. 114, No. 19, pp. 3983-3993. Prepublished online as a Blood First Edition Paper on August 10, 2009; DOI 10.1182/blood-2009-06-227603. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2009-06-227603v1 114/19/3983    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Heuser, M. Articles by Humphries, R. K. PubMed PubMed Citation Articles by Heuser, M. Articles by Humphries, R. K. Related Collections Plenary Papers Myeloid Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLENARY PAPER Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal Michael Heuser1,2, Laura M. Sly1, Bob Argiropoulos1, Florian Kuchenbauer1, Courteney Lai1, Andrew Weng1, Malina Leung1, Grace Lin1, Christy Brookes1, Stephen Fung1, Peter J. Valk3, Ruud Delwel3, Bob Löwenberg3, Gerald Krystal1, and R. Keith Humphries1,4 1 Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC; 2 Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; 3 Department of Hematology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands; and 4 Department of Medicine, University of British Columbia, Vancouver, BC Although the cancer stem cell (CSC) concept implies that CSCs are rare, recent reports suggest that CSCs may be frequent in some cancers. We hypothesized that the proportion of leukemia stem cells would vary as a function of the number of dysregulated pathways. Constitutive expression of MN1 served as a 1-oncogene model, and coexpression of MN1 and a HOX gene served as a 2-oncogene model. Leukemia-initiating cell (LIC) number and in vitro expansion potential of LICs were functionally assessed by limiting dilution analyses. LIC expansion potential was 132-fold increased in the 2- compared with the 1-oncogene model, although phenotypically, both leukemias were similar. The 2-oncogene model was characterized by granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity and activated STAT/ERK signaling. GM-CSF hypersensitivity of the 2-oncogene model (MN1/HOXA9) was lost in Stat5b–/– cells, and the LIC expansion potential was reduced by 86- and 28-fold in Stat5b–/– and Stat1–/– cells, respectively. Interestingly, in 201 acute myeloid leukemia (AML) patients, coexpression of MN1 and HOXA9 was restricted to patients with the poorest prognosis and was associated with highly active STAT signaling. Our data demonstrate the functional heterogeneity of LICs and show that STAT signaling is critical for leukemia stem cell self-renewal in MN1- and HOXA9-expressing leukemias. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Heterogeneity in the AML stem cell pool Laura E. Hays Blood 2009 114: 3976-3977. [Full Text] [PDF] This article has been cited by other articles: L. E. Hays Heterogeneity in the AML stem cell pool Blood, November 5, 2009; 114(19): 3976 - 3977. [Full Text] [PDF]

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