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The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML.

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/beta-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/beta-catenin pathway is normally active in HSCs but not in GMP, these results suggest that reactivation of beta-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. beta-catenin is not absolutely required for self-renewal of adult HSCs; thus, targeting the Wnt/beta-catenin pathway may represent a new therapeutic opportunity in AML.

SUBMITTER: Wang Y

PROVIDER: S-EPMC3084586 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML.

Wang Yingzi Y Krivtsov Andrei V AV Sinha Amit U AU North Trista E TE Goessling Wolfram W Feng Zhaohui Z Zon Leonard I LI Armstrong Scott A SA

Science (New York, N.Y.) 20100301 5973

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/beta-catenin signal ...[more]

PMID: 20339075

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Project description:BackgroundBeta-catenin is an essential mediator of canonical Wnt signaling and a central component of the cadherin-catenin epithelial adhesion complex. Dysregulation of beta-catenin expression has been described in pancreatic neoplasia. Newly published studies have suggested that beta-catenin is critical for normal pancreatic development although these reports reached somewhat different conclusions. In addition, the molecular mechanisms by which loss of beta-catenin affects pancreas development are not well understood. The goals of this study then were; 1] to further investigate the role of beta-catenin in pancreatic development using a conditional knockout approach and 2] to identify possible mechanisms by which loss of beta-catenin disrupts pancreatic development. A Pdx1-cre mouse line was used to delete a floxed beta-catenin allele specifically in the developing pancreas, and embryonic pancreata were studied by immunohistochemistry and microarray analysis.ResultsPdx1-cre floxed beta-catenin animals were viable but demonstrated small body size and shortened median survival. The pancreata from knockout mice were hypoplastic and histologically demonstrated a striking paucity of exocrine pancreas, acinar to duct metaplasia, but generally intact pancreatic islets containing all lineages of endocrine cells. In animals with extensive acinar hypoplasia, putative hepatocyte transdifferention was occasionally observed. Obvious and uniform pancreatic hypoplasia was observed by embryonic day E16.5. Transcriptional profiling of Pdx1-cre floxed beta-catenin embryonic pancreata at E14.5, before there was a morphological phenotype, revealed significant decreases in the beta-catenin target gene N-myc, and the basic HLH transcription factor PTF1, and an increase of several pancreatic zymogens compared to control animals. By E16.5, there was a dramatic loss of exocrine markers and an increase in Hoxb4, which is normally expressed anterior to the pancreas.ConclusionWe conclude that beta-catenin expression is required for development of the exocrine pancreas, but is not required for development of the endocrine compartment. In contrast, beta-catenin/Wnt signaling appears to be critical for proliferation of PTF1+ nascent acinar cells and may also function, in part, to maintain an undifferentiated state in exocrine/acinar cell precursors. Finally, beta-catenin may be required to maintain positional identity of the pancreatic endoderm along the anterior-posterior axis. This data is consistent with the findings of frequent beta-catenin mutations in carcinomas of acinar cell lineage seen in humans.

Dataset Information

The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML.

Publications

The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML.

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