A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia-like syndrome in BXH-2 mice.
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-gamma 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.
Turcotte
Karine
K
Department of Biochemistry, McGill Cancer Center, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Gauthier
Susan
S
Tuite
Ashleigh
A
Mullick
Alaka
A
Malo
Danielle
D
Gros
Philippe
P
D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D001120:Arginine / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics; D003545:Cysteine / Q000235:genetics; D020022:Genetic Predisposition to Disease; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000821:virology; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000503:physiopathology / Q000821:virology; D051379:Mice; D016254:Mutagenesis, Insertional / Q000235:genetics / Q000502:physiology; D009163:Mycobacterium bovis; D017354:Point Mutation; D040641:Quantitative Trait Loci / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D012190:Retroviridae / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000503:physiopathology; D014376:Tuberculosis / Q000235:genetics / Q000662:veterinary* / Q000821:virology; D014779:Virus Replication / Q000235:genetics / Q000502:physiology; D000099185:Interferon Regulatory Factor-8
D001120:Arginine; D003545:Cysteine; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D018664:Interleukin-12; D012333:RNA, Messenger; D012097:Repressor Proteins; D000099185:Interferon Regulatory Factor-8