CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling

• Published in: The Journal of clinical investigation 2013-01, Vol.123 (1), p.299-314
• Main Authors: Faber, Katrin, Bullinger, Lars, Ragu, Christine, Garding, Angela, Mertens, Daniel, Miller, Christina, Martin, Daniela, Walcher, Daniel, Döhner, Konstanze, Döhner, Hartmut, Claus, Rainer, Plass, Christoph, Sykes, Stephen M, Lane, Steven W, Scholl, Claudia, Fröhling, Stefan
• Format: Article
• Language: English
• Subjects: Animals; CDX2 Transcription Factor; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Gene expression; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; HL-60 Cells; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; K562 Cells; Kruppel-Like Transcription Factors - biosynthesis; Kruppel-Like Transcription Factors - genetics; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; Organ Specificity - genetics; PPAR gamma - genetics; PPAR gamma - metabolism; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; U937 Cells
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI64745

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.