Oncotarget

Research Papers:

VENTX induces expansion of primitive erythroid cells and contributes to the development of acute myeloid leukemia in mice

Eva Gentner _, Naidu M. Vegi, Medhanie A. Mulaw, Tamoghna Mandal, Shiva Bamezai, Rainer Claus, Alpaslan Tasdogan, Leticia Quintanilla-Martinez, Alexander Grunenberg, Konstanze Döhner, Hartmut Döhner, Lars Bullinger, Torsten Haferlach, Christian Buske, Vijay P.S. Rawat and Michaela Feuring-Buske

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Oncotarget. 2016; 7:86889-86901. https://doi.org/10.18632/oncotarget.13563

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Abstract

Eva Gentner1, Naidu M. Vegi1, Medhanie A. Mulaw1, Tamoghna Mandal1, Shiva Bamezai1, Rainer Claus2, Alpaslan Tasdogan3, Leticia Quintanilla-Martinez4, Alexander Grunenberg5, Konstanze Döhner5, Hartmut Döhner5, Lars Bullinger5, Torsten Haferlach6, Christian Buske1, Vijay P.S. Rawat1,*, Michaela Feuring-Buske5,*

1Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081 Ulm, Germany

2Department of Internal Medicine I, University Hospital Freiburg, 79106 Freiburg, Germany

3Institute of Immunology, Ulm University, 89081 Ulm, Germany

4Institute of Pathology, University of Tübingen, 72076 Tübingen, Germany

5Department of Internal Medicine III, University Hospital Ulm, 89081 Ulm, Germany

6MLL Munich Leukemia Laboratory, 81377 Munich, Germany

*These authors have contributed equally to this work

Correspondence to:

Michaela Feuring-Buske, email: [email protected]

Keywords: acute erythroleukemia, VENTX, AML1-ETO, homeobox gene, embryonic transcription factor

Received: August 12, 2016     Accepted: November 09, 2016     Published: November 24, 2016

ABSTRACT

Homeobox genes are key regulators in normal and malignant hematopoiesis. The human Vent-like homeobox gene VENTX, a putative homolog of the Xenopus laevis Xvent-2 gene, was shown to be highly expressed in normal myeloid cells and in patients with acute myeloid leukemia. We now demonstrate that constitutive expression of VENTX suppresses expression of genes responsible for terminal erythroid differentiation in normal CD34+ stem and progenitor cells. Transplantation of bone marrow progenitor cells retrovirally engineered to express VENTX caused massive expansion of primitive erythroid cells and partly acute erythroleukemia in transplanted mice. The leukemogenic potential of VENTX was confirmed in the AML1-ETO transplantation model, as in contrast to AML1-ETO alone co-expression of AML1-ETO and VENTX induced acute myeloid leukemia, partly expressing erythroid markers, in all transplanted mice. VENTX was highly expressed in patients with primary human erythroleukemias and knockdown of VENTX in the erythroleukemic HEL cell line significantly blocked cell growth. In summary, these data indicate that VENTX is able to perturb erythroid differentiation and to contribute to myeloid leukemogenesis when co-expressed with appropriate AML oncogenes and point to its potential significance as a novel therapeutic target in AML.


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