title: 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.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Faber
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Christine
authors.initials: C
authors.lastname: Ragu
authors.forename: Angela
authors.initials: A
authors.lastname: Garding
authors.forename: Daniel
authors.initials: D
authors.lastname: Mertens
authors.forename: Christina
authors.initials: C
authors.lastname: Miller
authors.forename: Daniela
authors.initials: D
authors.lastname: Martin
authors.forename: Daniel
authors.initials: D
authors.lastname: Walcher
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Sykes
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009928:Organ Specificity / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D047495:PPAR gamma; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins