CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling

Faber, Katrin, Bullinger, Lars, Ragu, Christine, Garding, Angela, Mertens, Daniel, Miller, Christina, Martin, Daniela, Walcher, Daniel, Doehner, Konstanze, Doehner, Hartmut, Claus, Rainer, Plass, Christoph, Sykes, Stephen M., Lane, Steven W., Scholl, Claudia and Froehling, Stefan (2013) CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling. Journal of Clinical Investigation, 123 1: 299-314. doi:10.1172/JCI64745


Author Faber, Katrin
Bullinger, Lars
Ragu, Christine
Garding, Angela
Mertens, Daniel
Miller, Christina
Martin, Daniela
Walcher, Daniel
Doehner, Konstanze
Doehner, Hartmut
Claus, Rainer
Plass, Christoph
Sykes, Stephen M.
Lane, Steven W.
Scholl, Claudia
Froehling, Stefan
Title CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling
Journal name Journal of Clinical Investigation   Check publisher's open access policy
ISSN 0021-9738
1708-8267
Publication date 2013-01-02
Sub-type Article (original research)
DOI 10.1172/JCI64745
Open Access Status Not Open Access
Volume 123
Issue 1
Start page 299
End page 314
Total pages 16
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Language eng
Abstract 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.
Keyword CDX2-driven leukemogenesis
KLF4 repression
Deregulated PPARγ signaling
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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