The Journal of Experimental Medicine
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Published 21 March 2005. doi:10.1084/jem.20042170
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 6, 881-890
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ARTICLE

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

Karine Turcotte1,2, Susan Gauthier1,2, Ashleigh Tuite1,2, Alaka Mullick3, Danielle Malo2, and Philippe Gros1,2

1 Department of Biochemistry, McGill Cancer Center
2 Center for the Study of Host Resistance, Department of Human Genetics, McGill University, Montreal, Quebec H3G 1Y6, Canada
3 Biotechnology Research Institute, Montreal, Quebec H4P 2R2, Canada

CORRESPONDENCE Philippe Gros: philippe.gros{at}mcgill.ca

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.

Abbreviations used: CML, chronic myeloid leukemia; DBD, DNA-binding domain; IAD, IRF association domain; MuLV, murine leukemia virus, SNP, single nucleotide polymorphism.


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