Retroviral integration at the Epi1 locus cooperates with Nf1 gene loss in the progression to acute myeloid leukemia

Juvenile myelomonocytic leukemia (JMML) is a disease that occurs in young c hildren and is associated with a high mortality rate. In most patients, JMM L has a progressive course leading to death by virtue of infection, bleedin g, or progression to acute myeloid leukemia (AML). As it is known that chil dren with neurofibromatosis type 1 syndrome have a markedly increased risk of developing JMML, we have previously developed a mouse model of JMML thro ugh reconstitution of lethally irradiated mice with hematopoietic stem cell s homozygous for a loss-of-function mutation in the Nf1 gene (D. L. Largaes pada, 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 gen etically identical reconstituted mice developed a JMML-like disorder, but o nly a subset went on to develop more acute disease. This result strongly su ggests that additional genetic lesions are responsible for disease progress ion to AML. Here, we describe the production of a unique tumor panel, creat ed using the BXH-2 genetic background, for identification of these addition al genetic lesions. Using this tumor panel, we have identified a locus, Epi 1, 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 s uggest that proviral integrations at Epi1 cooperate with loss of Nf1 to cau se AML.