A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia-like syndrome in BXH-2 mice

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DOIResolve DOI: http://doi.org/10.1084/jem.20042170
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TypeArticle
Journal titleThe Journal of Experimental Medicine
Volume201
Issue6
Pages881890; # of pages: 10
SubjectAmino Acid Substitution; Animals; Arginine; bio; biosynthesis; Cells; Chromosomes,Mammalian; Cysteine; cytology; Genetic Predisposition to Disease; genetics; Immunologic Deficiency Syndromes; Interferon Regulatory Factors; Interferon Type II; Interleukin-12; Leukemia,Myeloid; Mice; Mutagenesis; Mutagenesis,Insertional; Mutation; Mycobacterium bovis; Oncogenes; physiology; physiopathology; Point Mutation; Protein; Proteins; Quantitative Trait Loci; Repressor Proteins; Retroviridae; Rna; Spleen; Tuberculosis; veterinary; virology; Virus Replication
AbstractBXH-2 mice develop a fatal myeloid leukemia by a two-step mutagenic process. First, a BXH-2-specific recessive mutation causes a myeloproliferative syndrome. Second, retroviral insertions alter oncogenes or tumor suppressors, resulting in clonal expansion of leukemic cells. We have identified a recessive locus on chromosome 8 (Myls) that is responsible for myeloproliferation in BXH-2. This Myls interval has been narrowed down to 2 Mb and found to contain several positional candidates, including the interferon consensus sequence-binding protein 1 gene (Icsbp, also known as interferon regulatory factor 8 [IRF8]). we show that BXH-2 mice carry a mutation (915 C to T) resulting in an arginine-to-cysteine substitution at position 294 within the predicted IRF association domain of the protein. Although expression of Icsbp1 mRNA transcripts is normal in BXH-2 splenocytes, these cells are unable to produce interleukin 12 and interferon-γ in response to activating stimuli, confirming the R294C behaves as a loss-of-function mutation. Myeloproliferation in BXH-2 mice is concomitant to increased susceptibility to Mycobacterium bovis (BCG) despite the presence of resistance alleles at the Nramp1 locus. These results suggest a two-step model for chronic myeloid leukemia in BXH-2, in which inactivation of Icsbp1 predisposes to myeloproliferation and immunodeficiency. This even is required for retroviral replication, and subsequent insertional mutagenesis that causes leukemia in BXH-2 mice.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada; NRC Biotechnology Research Institute
Peer reviewedNo
NRC number47802
NPARC number3540260
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Record identifier56154d30-9819-4929-8d01-0600ad396e56
Record created2009-03-01
Record modified2016-05-09
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