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

• DOI: 10.1084/jem.20042170
• Publication Date: 2005-03-21T19:32:53Z
• Authors: Karine Turcotte; Susan Gauthier; Ashleigh Tuite; Alaka Mullick; Danielle Malo; Philippe Gros
• Keywords: 0301 basic medicine; Cells; Quantitative Trait Loci; Mutagenesis,Insertional; Leukemia,Myeloid; Virus Replication; Arginine; Article; Interferon-gamma; Mice; 03 medical and health sciences; Tuberculosis; Animals; Point Mutation; genetics; Genetic Predisposition to Disease; Cysteine; RNA, Messenger; Interferon Type II; Protein; Immunologic Deficiency Syndromes; Proteins; Oncogenes; veterinary; Chromosomes, Mammalian; Interleukin-12; Mycobacterium bovis; virology; 3. Good health; Repressor Proteins; Mutagenesis, Insertional; Chromosomes,Mammalian; Retroviridae; Amino Acid Substitution; Mutagenesis; Leukemia, Myeloid; Mutation; physiology; Interferon Regulatory Factors; cytology; Rna; biosynthesis; physiopathology; Spleen; biotechnology

BXH-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 that 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 event is required for retroviral replication, and subsequent insertional mutagenesis that causes leukemia in BXH-2 mice.