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Science 327 (5973): 1650-1653

Copyright © 2010 by the American Association for the Advancement of Science

The Wnt/β-Catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML

Yingzi Wang,1 Andrei V. Krivtsov,1 Amit U. Sinha,1,2 Trista E. North,3,4 Wolfram Goessling,4,5,6 Zhaohui Feng,1,2 Leonard I. Zon,1,4,7 Scott A. Armstrong1,2,4,*

Abstract: Leukemia stem cells (LSCs) are capable of limitless self-renewal and are responsible for the maintenance of leukemia. Because selective eradication of LSCs could offer substantial therapeutic benefit, there is interest in identifying the signaling pathways that control their development. We studied LSCs in mouse models of acute myelogenous leukemia (AML) induced either by coexpression of the Hoxa9 and Meis1a oncogenes or by the fusion oncoprotein MLL-AF9. We show that the Wnt/β-catenin signaling pathway is required for self-renewal of LSCs that are derived from either hematopoietic stem cells (HSC) or more differentiated granulocyte-macrophage progenitors (GMP). Because the Wnt/β-catenin pathway is normally active in HSCs but not in GMP, these results suggest that reactivation of β-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. β-catenin is not absolutely required for self-renewal of adult HSCs; thus, targeting the Wnt/β-catenin pathway may represent a new therapeutic opportunity in AML.

1 Division of Hematology/Oncology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Pediatric Oncology, Harvard Medical School, Boston, MA 02115, USA.
3 Department of Pathology, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, MA 02115, USA.
4 Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
5 Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
6 Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
7 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

* To whom correspondence should be addressed. E-mail: scott.armstrong{at}childrens.harvard.edu

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