CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling
Katrin Faber, … , Claudia Scholl, Stefan Fröhling
Katrin Faber, … , Claudia Scholl, Stefan Fröhling
Published December 3, 2012
Citation Information: J Clin Invest. 2013;123(1):299-314. https://doi.org/10.1172/JCI64745.
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Research Article Oncology

CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling

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.

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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Figure 4

Reversal of CDX2-induced transcriptional changes by PPARγ agonist treatment, and deregulated PPARγ signaling in CDX2-driven AML.

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Reversal of CDX2-induced transcriptional changes by PPARγ agonist treatm...
(A) C-Map–based identification of PPARγ agonists among small bioactive molecules negatively linked to a gene signature associated with Cdx2 expression in murine c-Kit+Lin– HSPCs. The red region in the bar plot indicates compounds with a negative enrichment score. Molecules are ordered according to decreasing similarity to Cdx2. (B) Treatment with 5 μM PGJ2 or 50 μM telmisartan for 24 hours increased KLF4 mRNA expression in CDX2+ NOMO-1 and SKM-1 cells, but not in CDX2– K-562 and HEL cells. (C) Pretreatment with 2 μM T0070907 for 2 hours partially reversed the effect of PGJ2 on KLF4 mRNA expression in NOMO-1 and SKM-1 cells. (D) PPARG and PPARGC1A mRNA expression in human myeloid leukemia cell lines. (E) BMT experiments. GEP, gene expression profiling. (F) Relative differential expression of components of BioCarta Pathway “Role of PPAR-gamma Coactivators in Obesity and Thermogenesis” between Cdx2 and MLL murine leukemias. Ppargc1a was the top differentially expressed gene, showing a 30-fold upregulation in Cdx2-induced AML. In addition, overexpression of Cdx2 and repression of Klf4 in Cdx2 leukemias are shown.