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.
View: Text | PDF
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

×

Figure 3

Growth-inhibitory effect of KLF4 in CDX2+ human myeloid leukemia cell lines and murine AML.

Options: View larger image (or click on image) Download as PowerPoint
Growth-inhibitory effect of KLF4 in CDX2+ human myeloid leukemia cell li...
(A) Effects of KLF4 on viability and proliferation of human myeloid leukemia cell lines. (B) Effects of KLF4 on viability and proliferation of early-passage cell lines derived from Cdx2-induced murine leukemias. (C) Apoptosis induction by KLF4 in CDX2+ NOMO-1 cells, but not in CDX2– K-562 cells. (D) Colony formation of AML cells in response to CDX2 and KLF4 knockdown. CDX2+ NOMO-1 cells were stably transduced with combinations of shRNAs and plated in methylcellulose. Knockdown of CDX2 (shCDX2_1/shControl) reduced the number of colonies. Colony formation was partially rescued by concomitant knockdown of KLF4 (shKLF4_1/shCDX2_1). Representative photomicrographs of methylcellulose cultures are shown. Original magnification, ×4.7. (E) CDX2+ NOMO-1 cells stably transduced with an shRNA targeting KLF4 or a nontargeting control shRNA were transduced with a lentiviral vector coexpressing GFP with an shRNA targeting CDX2 or a nontargeting control shRNA. The GFP+ fraction was measured by flow cytometry at the indicated time points. Knockdown of CDX2 alone (shCDX2_1/shControl) depleted GFP+ cells over time. The proportion of GFP+ cells was rescued by concomitant knockdown of KLF4 (shKLF4_1/shCDX2_1). (F) Competitive BMT experiments (n = 4 per group). (G) Proportion of GFP+THY1+ cells in the BM and spleen of mice in F. (H) Noncompetitive BMT experiments (n = 10 per group). (I) Survival of mice in H.