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PMID: 14718672 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Ectopic expression of the homeobox gene Cdx2 is the transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 3 ·2004-01-20 ·Pages 817-22

Rawat VP, Cusan M, Deshpande A, Hiddemann W, Quintanilla-Martinez L, Humphries RK, Bohlander SK, Feuring-Buske M, Buske C

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.

MeSH Terms
Animals Bone Marrow Transplantation CDX2 Transcription Factor Cell Transformation, Neoplastic/genetics Chromosomes, Human, Pair 12/genetics Chromosomes, Human, Pair 13/genetics Disease Models, Animal Gene Expression Genes, Homeobox Homeodomain Proteins/genetics Humans Leukemia, Myeloid, Acute/genetics,pathology Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Transgenic Myeloid Ecotropic Viral Integration Site 1 Protein Neoplasm Proteins/genetics Oncogene Proteins, Fusion/genetics Trans-Activators Translocation, Genetic
Chemicals
CDX2 Transcription Factor ETV6-CDX2 protein, human Homeodomain Proteins Myeloid Ecotropic Viral Integration Site 1 Protein Neoplasm Proteins Oncogene Proteins, Fusion Trans-Activators homeobox protein HOXA9
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Rawat Vijay P S
GSF-Clinical Cooperative Group Leukemia and Department of Medicine III, Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany.
Cusan Monica
Deshpande Aniruddha
Hiddemann Wolfgang
Quintanilla-Martinez Leticia
Humphries R Keith
Bohlander Stefan K
Feuring-Buske Michaela
Buske Christian
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0305555101
Published
2004-01-20
Epub
2004-00-12
Pages
817-22
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC321764
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0305555101 PMC Full Text View journal details
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