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Acute Leukemias

The homeobox gene CDX2 is aberrantly expressed and associated with an inferior prognosis in patients with acute lymphoblastic leukemia

Leukemia volume 23, pages 649–655 (2009)Cite this article

Abstract

Molecular characterization of acute lymphoblastic leukemia (ALL) has greatly improved the ability to categorize and prognostify patients with this disease. In this study, we show that the proto-oncogene CDX2 is aberrantly expressed in the majority of cases with B-lineage ALL and T-ALL. High expression of CDX2 correlated significantly with the ALL subtype pro-B ALL, cALL, Ph+ ALL and early T-ALL. Furthermore, high expression of CDX2 was associated with inferior overall survival and showed up as a novel and strong risk factor for ALL in bivariate analysis. Functional analyses showed that overexpression of Cdx2 in murine bone marrow progenitors perturbed genes involved in lymphoid development and that depletion of CDX2 in the human ALL cell line Nalm6 inhibited colony formation. These data indicate that aberrant CDX2 expression occurs frequently and has prognostic impact in adult patients with ALL.

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References

  1. Pui CH, Evans WE . Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354: 166–178.

    Article  CAS  PubMed  Google Scholar 

  2. Gokbuget N, Hoelzer D . Treatment of adult acute lymphoblastic leukemia. Hematol Am Soc Hematol Educ Program 2006; 1: 133–141.

    Article  Google Scholar 

  3. Armstrong SA, Look AT . Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol 2005; 23: 6306–6315.

    Article  CAS  PubMed  Google Scholar 

  4. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446: 758–764.

    Article  CAS  PubMed  Google Scholar 

  5. Paulsson K, Cazier JB, Macdougall F, Stevens J, Stasevich I, Vrcelj N et al. Microdeletions are a general feature of adult and adolescent acute lymphoblastic leukemia: unexpected similarities with pediatric disease. Proc Natl Acad Sci USA 2008; 105: 6708–6713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chase A, Reiter A, Burci L, Cazzaniga G, Biondi A, Pickard J et al. Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). Blood 1999; 93: 1025–1031.

    CAS  PubMed  Google Scholar 

  7. Rawat VP, Cusan M, Deshpande A, Hiddemann W, Quintanilla-Martinez L, Humphries RK et al. Ectopic expression of the homeobox gene Cdx2 is the transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia. Proc Natl Acad Sci USA 2004; 101: 817–822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Scholl C, Bansal D, Dohner K, Eiwen K, Huntly BJ, Lee BH et al. The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis. J Clin Invest 2007; 117: 1037–1048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Brooke NM, Garcia-Fernandez J, Holland PW . The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster. Nature 1998; 392: 920–922.

    Article  CAS  PubMed  Google Scholar 

  10. Suh E, Traber PG . An intestine-specific homeobox gene regulates proliferation and differentiation. Mol Cell Biol 1996; 16: 619–625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rawat VP, Thoene S, Naidu VM, Arseni N, Heilmeier B, Metzeler K et al. Overexpression of CDX2 perturbs HOX gene expression in murine progenitors depending on its N-terminal domain and is closely correlated with deregulated HOX gene expression in human acute myeloid leukemia. Blood 2008; 111: 309–319.

    Article  CAS  PubMed  Google Scholar 

  12. Wang Y, Yabuuchi A, McKinney-Freeman S, Ducharme DM, Ray MK, Chawengsaksophak K et al. Cdx gene deficiency compromises embryonic hematopoiesis in the mouse. Proc Natl Acad Sci USA 2008; 105: 7756–7761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Raff T, Gokbuget N, Luschen S, Reutzel R, Ritgen M, Irmer S et al. Molecular relapse in adult standard-risk ALL patients detected by prospective MRD monitoring during and after maintenance treatment: data from the GMALL 06/99 and 07/03 trials. Blood 2007; 109: 910–915.

    Article  CAS  PubMed  Google Scholar 

  14. Ahmed F, Arseni N, Glimm H, Hiddemann W, Buske C, Feuring-Buske M . Constitutive expression of the ATP-binding cassette transporter ABCG2 enhances the growth potential of early human hematopoietic progenitors. Stem Cells 2008; 26: 810–818.

    Article  CAS  PubMed  Google Scholar 

  15. Yuasa Y, Nagasaki H, Akiyama Y, Sakai H, Nakajima T, Ohkura Y et al. Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients. Carcinogenesis 2005; 26: 193–200.

    Article  CAS  PubMed  Google Scholar 

  16. Bansal D, Scholl C, Frohling S, McDowell E, Lee BH, Dohner K et al. Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model. Proc Natl Acad Sci USA 2006; 103: 16924–16929.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Petropoulos K, Arseni N, Schessl C, Stadler CR, Rawat VP, Deshpande AJ et al. A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis. J Exp Med 2008; 205: 515–522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Bianka Ksienzyk and Nicole Behm for their excellent technical assistance, and the members of the animal facility at the Helmholtz Center Munich for their excellent breeding and maintenance of the animals. VPSR and CB and their work were supported by a grant of the DFG (SFB 684 project A7), MF-B by the Deutsche Krebshilfe (70-2968-Fe I to MFB) and the DFG (SFB 684 project A8), SKB by the DFG (SFB 684 project A6), CB, MF-B and SKB by the Bundesministerium für Bildung und Forschung (NGFN2 Grant 01GS0448) and DH by the Deutsche Krebshilfe (70-2657-Ho2).

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Author notes

  1. S Thoene and V P S Rawat: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine III, Klinikum Grosshadern, Munich, Germany

    S Thoene, V P S Rawat, B Heilmeier, E Hoster, K H Metzeler, T Herold, W Hiddemann, S K Bohlander, M Feuring-Buske & C Buske

  2. Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, Munich, Germany

    S Thoene, V P S Rawat, W Hiddemann, S K Bohlander, M Feuring-Buske & C Buske

  3. Department of Medicine III, Johann Wolfgang Goethe University, Frankfurt/Main, Germany

    N Gökbuget & D Hoelzer

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  1. S Thoene
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  2. V P S Rawat
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  3. B Heilmeier
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  7. W Hiddemann
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  12. C Buske
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Correspondence to C Buske.

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Thoene, S., Rawat, V., Heilmeier, B. et al. The homeobox gene CDX2 is aberrantly expressed and associated with an inferior prognosis in patients with acute lymphoblastic leukemia. Leukemia 23, 649–655 (2009). https://doi.org/10.1038/leu.2008.355

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