The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis
Claudia Scholl, … , D. Gary Gilliland, Stefan Fröhling
Claudia Scholl, … , D. Gary Gilliland, Stefan Fröhling
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):1037-1048. https://doi.org/10.1172/JCI30182.
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Research Article

The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis

Abstract

The homeobox transcription factor CDX2 plays an important role in embryonic development and regulates the proliferation and differentiation of intestinal epithelial cells in the adult. We have found that CDX2 is expressed in leukemic cells of 90% of patients with acute myeloid leukemia (AML) but not in hematopoietic stem and progenitor cells derived from normal individuals. Stable knockdown of CDX2 expression by RNA interference inhibited the proliferation of various human AML cell lines and strongly reduced their clonogenic potential in vitro. Primary murine hematopoietic progenitor cells transduced with Cdx2 acquired serial replating activity, were able to be continuously propagated in liquid culture, generated fully penetrant and transplantable AML in BM transplant recipients, and displayed dysregulated expression of Hox family members in vitro and in vivo. These results demonstrate that aberrant expression of the developmental regulatory gene CDX2 in the adult hematopoietic compartment is a frequent event in the pathogenesis of AML; suggest a role for CDX2 as part of a common effector pathway that promotes the proliferative capacity and self-renewal potential of myeloid progenitor cells; and support the hypothesis that CDX2 is responsible, in part, for the altered HOX gene expression that is observed in most cases of AML.

Authors

Claudia Scholl, Dimple Bansal, Konstanze Döhner, Karina Eiwen, Brian J.P. Huntly, Benjamin H. Lee, Frank G. Rücker, Richard F. Schlenk, Lars Bullinger, Hartmut Döhner, D. Gary Gilliland, Stefan Fröhling

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Figure 3

Colony formation of AML cell lines after shRNA-mediated silencing of CDX2 expression.

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Colony formation of AML cell lines after shRNA-mediated silencing of CDX...
(A) Colony-forming assays showed a significant reduction in the number of colonies for the 5 CDX2-expressing cell lines SKM-1, MV4-11 (1 × 104 plated cells), THP-1, MOLM-14, and NOMO-1 (1 × 103 plated cells) after CDX2 mRNA knockdown by shRNA TRCN13684 as compared with cells transduced with the nonsilencing control construct. In contrast, transduction with shRNA TRCN13684 did not reduce colony formation of EOL-1, which had a very high CDX2 expression level (37,388; 82% mRNA knockdown; estimated residual expression level, 6,730); MONO-MAC-6, in which CDX2 expression was not efficiently silenced (4% mRNA knockdown); and HL-60 and K-562, which do not express CDX2 mRNA. Experiments were performed in duplicate. Values are represented as mean ± SEM. *P < 0.05; **P < 0.001. (B and C) Microscopic analysis of colonies derived from shRNA-transduced cells (right panels) showed a decrease in the number of colonies and the number of cells per colony, as compared with cells transduced with the nonsilencing control construct (left panels), for CDX2-expressing cell lines but not for CDX2-negative K-562 cells. Representative photomicrographs of methylcellulose cultures are shown. Original magnification, ×20 and ×100, respectively. (D) CDX2-expressing AML cell lines showed varying absolute mRNA levels after shRNA-mediated CDX2 knockdown.