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Journal of Virology, October 2001, p. 9427-9434, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9427-9434.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Retroviral Integration at the Epi1 Locus Cooperates with Nf1 Gene Loss in the Progression to Acute Myeloid Leukemia

Susan M. Blaydes,1 Scott C. Kogan,2 Bao-Tran H. Truong,2 Debra J. Gilbert,3 Nancy A. Jenkins,3 Neal G. Copeland,3 David A. Largaespada,4 and Camilynn I. Brannan1,*

Department of Molecular Genetics and Microbiology, Center for Mammalian Genetics, and University of Florida Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida 326101; Department of Laboratory Medicine, Comprehensive Cancer Center, University of California---San Francisco, San Francisco, California 941432; Mouse Cancer Genetics Program, National Cancer Institute---Frederick, Frederick, Maryland 217023; and Department of Genetics, Cell Biology and Development, University of Minnesota Cancer Center, Minneapolis, Minnesota 554554

Received 29 March 2001/Accepted 19 June 2001

Juvenile myelomonocytic leukemia (JMML) is a disease that occurs in young children and is associated with a high mortality rate. In most patients, JMML has a progressive course leading to death by virtue of infection, bleeding, or progression to acute myeloid leukemia (AML). As it is known that children with neurofibromatosis type 1 syndrome have a markedly increased risk of developing JMML, we have previously developed a mouse model of JMML through reconstitution of lethally irradiated mice with hematopoietic stem cells homozygous for a loss-of-function mutation in the Nf1 gene (D. L. Largaespada, C. I. Brannan, N. A. Jenkins, and N. G. Copeland, Nat. Genet. 12:137-143, 1996). In the course of these experiments, we found that all these genetically identical reconstituted mice developed a JMML-like disorder, but only a subset went on to develop more acute disease. This result strongly suggests that additional genetic lesions are responsible for disease progression to AML. Here, we describe the production of a unique tumor panel, created using the BXH-2 genetic background, for identification of these additional genetic lesions. Using this tumor panel, we have identified a locus, Epi1, which maps 30 to 40 kb downstream of the Myb gene and appears to be the most common site of somatic viral integration in BXH-2 mice. Our findings suggest that proviral integrations at Epi1 cooperate with loss of Nf1 to cause AML.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, P.O. Box 100266, University of Florida College of Medicine, Gainesville, FL 32610. Phone: (352) 392-3296. Fax: (352) 392-3133. E-mail: brannan{at}mgm.ufl.edu.

Journal of Virology, October 2001, p. 9427-9434, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9427-9434.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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