Ectopic expression of the homeobox gene Cdx2 is the transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia
- Vijay P. S. Rawat*,†,
- Monica Cusan*,†,
- Aniruddha Deshpande*,†,
- Wolfgang Hiddemann*,†,
- Leticia Quintanilla-Martinez‡,
- R. Keith Humphries§,¶,
- Stefan K. Bohlander*,†,
- Michaela Feuring-Buske*,†, and
- Christian Buske*,†,∥
- *GSF–Clinical Cooperative Group Leukemia and †Department of Medicine III, Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany; ‡GSF–Department of Pathology, 85764 Neuherberg, Germany; and §Terry Fox Laboratory, BC Cancer Agency and ¶Department of Medicine, University of British Columbia, Vancouver, BC, Canada V5Z 4E6
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Edited by Janet D. Rowley, University of Chicago Medical Center, Chicago, IL, and approved November 21, 2003 (received for review August 29, 2003)
Abstract
Creation of fusion genes by balanced chromosomal translocations is one of the hallmarks of acute myeloid leukemia (AML) and is considered one of the key leukemogenic events in this disease. In t(12;13)(p13;q12) AML, ectopic expression of the homeobox gene CDX2 was detected in addition to expression of the ETV6-CDX2 fusion gene, generated by the chromosomal translocation. Here we show in a murine model of t(12;13)(p13;q12) AML that myeloid leukemogenesis is induced by the ectopic expression of CDX2 and not by the ETV6-CDX2 chimeric gene. Mice transplanted with bone marrow cells retrovirally engineered to express Cdx2 rapidly succumbed to fatal and transplantable AML. The transforming capacity of Cdx2 depended on an intact homeodomain and the N-terminal transactivation domain. Transplantation of bone marrow cells expressing ETV6-CDX2 failed to induce leukemia. Furthermore, coexpression of ETV6-CDX2 and Cdx2 in bone marrow cells did not accelerate the course of disease in transplanted mice compared to Cdx2 alone. These data demonstrate that activation of a protooncogene by a balanced chromosomal translocation can be the pivotal leukemogenic event in AML, characterized by the expression of a leukemia-specific fusion gene. Furthermore, these findings link protooncogene activation to myeloid leukemogenesis, an oncogenic mechanism so far associated mainly with lymphoid leukemias and lymphomas.
Footnotes
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↵ ∥ To whom correspondence should be addressed. E-mail: buske{at}gsf.de.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: AML, acute myeloid leukemia; BM, bone marrow; YFP, yellow fluorescent protein; CFU-S, colony-forming unit–spleen; PB, peripheral blood.
- Copyright © 2004, The National Academy of Sciences
