| |
A mutation in IRF-8 causes myeloproliferation in the spleen which predisposes BXH-2 mice to leukemia.
|
|
New genetic mapping studies explain why a certain mouse strain is predisposed to developing fatal leukemia. Turcotte et al., reporting on page 881, identify a point mutation in the transcription factor IRF-8 (interferon regulatory factor 8) that abolishes its function and sets the stage for a second, leukemia-triggering mutation.
The recombinant mouse strain BXH-2 is known to develop first a myeloproliferative disease characterized by enlarged spleens with excess granulocytes, and later a spontaneous, fatal myeloid leukemia. The myeloproliferative disease is associated with a mutation at the Myls locus on chromosome 8, and the leukemia with insertion of an endogenous murine leukemia virus (MuLV) into host tumor suppressor genes.
The offending virus arises from a recombination event between two innocuous MuLV proviruses; they are carried in the genome of BXH mice but, before recombination, cannot produce replicating virus progeny. Eager to understand how the viral integration event was connected to the Myls locus, Turcotte and colleagues scoured the locus for genetic clues. Their search revealed an inactivating point mutation in IRF-8, a transcription factor that regulates interferon-responsive genes. The mutation was found only in strains that are susceptible to getting leukemia.
The IRF-8 mutation explained the myeloproliferative disease in the BXH-2 mice, as IRF-8–deficient mice were previously shown to have a similar phenotype. IRF-8–deficient mice also develop leukemia, but it is not as rapid or as severe as in BXH-2 mice, perhaps because these strains lack the MuLV proviruses. The authors think that the absence of IRF-8 is only the first hit in leukemia development. The excess cell division and faulty immune response caused by the loss of IRF-8, they suggest, must promote recombination that generates a replication-competent MuLV retrovirus that can then insert into the host genome.This may be a good model for human chronic myeloid leukemia (CML), which progresses from a chronic phase involving granulocytes to a rapidly fatal crisis stage. The authors are now looking for the homologue of IRF-8 in human CML tumors.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
