title: Retroviral integration at the Epi1 locus cooperates with Nf1 gene loss in the progression to acute myeloid leukemia.
abstract: 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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for Mammalian Genetics, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Blaydes
authors.forename: S C
authors.initials: SC
authors.lastname: Kogan
authors.forename: B T
authors.initials: BT
authors.lastname: Truong
authors.forename: D J
authors.initials: DJ
authors.lastname: Gilbert
authors.forename: N A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: N G
authors.initials: NG
authors.lastname: Copeland
authors.forename: D A
authors.initials: DA
authors.lastname: Largaespada
authors.forename: C I
authors.initials: CI
authors.lastname: Brannan
mesh_terms: D000208:Acute Disease; D000818:Animals; D017353:Gene Deletion; D016514:Genes, Neurofibromatosis 1; D020570:Genes, myb; D020022:Genetic Predisposition to Disease; D007942:Leukemia, Experimental / Q000209:etiology / Q000235:genetics* / Q000821:virology; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics* / Q000821:virology; D051379:Mice; D012190:Retroviridae / Q000235:genetics; D016662:Virus Integration / Q000235:genetics