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 2

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

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Proliferation of AML cell lines after shRNA-mediated silencing of CDX2 e...
(A) Downregulation of CDX2 expression by shRNA TRCN13684 inhibited proliferation of the CDX2-expressing AML cell lines SKM-1, THP-1, MV4-11, MOLM-14, and NOMO-1. In MONO-MAC-6 cells, shRNA TRCN13684 did not induce efficient CDX2 mRNA knockdown, and there was no effect on cell proliferation. Similarly, treatment with shRNA TRCN13684 had no inhibitory effect in the CDX2-negative cell lines HL-60 and K-562. For each of the 6 CDX2-expressing cell lines, the degree of mRNA knockdown is shown (inset) (SKM-1, 84%; THP-1, 68%; MV4-11, 52%; MOLM-14, 49%; NOMO-1, 23%; MONO-MAC-6, 4%). Experiments were performed in triplicate. Values are represented as mean ± SEM. (B) SKM-1 cells were transduced with a lentiviral vector that coexpresses shRNA TRCN13684 and GFP. Sorted cells (proportion of GFP+ cells, 98%) were cultured at a density of 0.5 × 106 to 1 × 106/ml, and the GFP+ fraction was measured by flow cytometry at the indicated time points. The toxicity of CDX2 knockdown was evidenced by a relative depletion of GFP+ cells over time. In contrast, analysis of SKM-1 cells transduced with a GFP-expressing pLKO.1 construct without an shRNA sequence (proportion of GFP+ cells, 95%) showed no decrease in the percentage of GFP+ cells. The degree of CDX2 mRNA knockdown is shown (inset; 93%).