Two strikes lead 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 Defenseless against the common cold Epithelial cell dysfunction may explain why people with asthma fare worse than most when infected with common cold viruses. Wark and colleagues show on page 937 that bronchial epithelial cells from asthma sufferers fail to invoke critical antiviral defenses but still provoke inflammation when infected with rhinoviruses—an ideal combination for asthma induction. Respiratory virus infections often trigger asthma attacks, and these infections are more severe in asthma sufferers than in healthy individuals. Past studies have demonstrated increased virus replication in asthmatic versus healthy subjects and suggested that alterations in cytokine production that favor asthma-promoting T helper (Th)-2 responses might be to blame. Wark and colleagues now uncover a defect that may provide the initial trigger for virus-induced asthma. They found that bronchial epithelial cells—the primary targets of 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, …