Document Detail


CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling.
MedLine Citation:
PMID:  23202735     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Aberrant expression of the homeodomain transcription factor CDX2 occurs in most cases of acute myeloid leukemia (AML) and promotes leukemogenesis, making CDX2, in principle, an attractive therapeutic target. Conversely, CDX2 acts as a tumor suppressor in colonic epithelium. The effectors mediating the leukemogenic activity of CDX2 and the mechanism underlying its context-dependent properties are poorly characterized, and strategies for interfering with CDX2 function in AML remain elusive. We report data implicating repression of the transcription factor KLF4 as important for the oncogenic activity of CDX2, and demonstrate that CDX2 differentially regulates KLF4 in AML versus colon cancer cells through a mechanism that involves tissue-specific patterns of promoter binding and epigenetic modifications. Furthermore, we identified deregulation of the PPARγ signaling pathway as a feature of CDX2-associated AML and observed that PPARγ agonists derepressed KLF4 and were preferentially toxic to CDX2+ leukemic cells. These data delineate transcriptional programs associated with CDX2 expression in hematopoietic cells, provide insight into the antagonistic duality of CDX2 function in AML versus colon cancer, and suggest reactivation of KLF4 expression, through modulation of PPARγ signaling, as a therapeutic modality in a large proportion of AML patients.
Authors:
Katrin Faber; Lars Bullinger; Christine Ragu; Angela Garding; Daniel Mertens; Christina Miller; Daniela Martin; Daniel Walcher; Konstanze Döhner; Hartmut Döhner; Rainer Claus; Christoph Plass; Stephen M Sykes; Steven W Lane; Claudia Scholl; Stefan Fröhling
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-03
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-02     Completed Date:  2013-03-11     Revised Date:  2014-07-09    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  299-314     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Colonic Neoplasms / genetics,  metabolism,  pathology
Gene Expression Regulation, Leukemic*
HL-60 Cells
Hematopoietic Stem Cells / metabolism,  pathology
Homeodomain Proteins / genetics,  metabolism*
Humans
K562 Cells
Kruppel-Like Transcription Factors / biosynthesis*,  genetics
Leukemia, Myeloid, Acute / genetics,  metabolism*,  pathology
Mice
Organ Specificity / genetics
PPAR gamma / genetics,  metabolism*
Signal Transduction*
Transcription Factors / genetics,  metabolism*
Tumor Suppressor Proteins / genetics,  metabolism
U937 Cells
Chemical
Reg. No./Substance:
0/CDX2 protein, human; 0/Cdx2 protein, mouse; 0/GKLF protein; 0/Homeodomain Proteins; 0/Kruppel-Like Transcription Factors; 0/PPAR gamma; 0/Transcription Factors; 0/Tumor Suppressor Proteins
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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