CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling

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Item Type:	Article
Title:	CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling
Creators Name:	Faber, K., Bullinger, L., Ragu, C., Garding, A., Mertens, D., Miller, C., Martin, D., Walcher, D., Döhner, K., Döhner, H., Claus, R., Plass, C., Sykes, S.M., Lane, S.W., Scholl, C. and Fröhling, S.
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.
Keywords:	CDX2 Transcription Factor, Colonic Neoplasms, Leukemic Gene Expression Regulation, HL-60 Cells, Hematopoietic Stem Cells, Homeodomain Proteins, K562 Cells, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors, Acute Myeloid Leukemia, Organ Specificity, PPAR gamma, Signal Transduction, Transcription Factors, Tumor Suppressor Proteins, Tumor Suppressor Proteins, U937 Cells, Animals, Mice
Source:	Journal of Clinical Investigation
ISSN:	1558-8238
Publisher:	American Society for Clinical Investigation
Volume:	123
Number:	1
Page Range:	299-314
Date:	2 January 2013
Official Publication:	https://doi.org/10.1172/JCI64745
PubMed:	View item in PubMed

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