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 4

In vitro self-renewal of murine BM and committed hematopoietic progenitor populations expressing Cdx2.

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In vitro self-renewal of murine BM and committed hematopoietic progenito...
(A) Whole primary murine BM expressing Cdx2 demonstrated replating potential to the fourth plating, whereas cells transduced with empty vector had a finite ability to serially replate. Experiments were performed in duplicate. Values are represented as mean ± SD. (B) Whole BM cells derived from the fourth plating could be expanded in IL-3-supplemented liquid culture. (C) Microscopic analysis of May-Grünwald-Giemsa–stained cytospin preparations of cells derived from the fourth plating demonstrated predominantly undifferentiated myeloid morphology. Original magnification, ×1,000. (D) Flow cytometric analysis of cells derived from the fourth plating showed expression of myeloid antigens and the immaturity markers Sca-1 and c-Kit and demonstrated the absence of CD3+ or B220+ lymphoid cells and Ter119+ erythroid cells. (E) Committed murine hematopoietic progenitors and HSCs expressing Cdx2 demonstrated replating potential to the fourth plating, whereas cells transduced with empty vector had a finite ability to serially replate. Experiments were performed in duplicate. Values are represented as mean ± SD. (F) Hematopoietic progenitors and HSCs derived from the fourth plating could be expanded in IL-3–supplemented liquid culture.