CDX2-driven Leukemogenesis Involves KLF4 Repression and Deregulated PPARγ Signaling

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2012 Dec 4

PMID 23202735

Citations 37

Authors

Katrin Faber

Lars Bullinger

Christine Ragu

Angela Garding

Daniel Mertens

Christina Miller

Daniela Martin

Daniel Walcher

Konstanze Dohner

Hartmut Dohner

Rainer Claus

Christoph Plass

Stephen M Sykes

Steven W Lane

Claudia Scholl

Stefan Frohling

Affiliations

Soon will be listed here.

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.

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