While studying the unique Nramp1 (Slcl1a1)-independent susceptibility of BXH-2 mice to Mycobacterium bovis (BCG) infection, we noted that these mice develop splenomegaly associated with important infiltration of Mac-1+/GR-1+ (macrophage antigen-1 +/granulocyte differentiation antigen 1+) granulocyte precursors in spleen, lymph nodes and bone marrow resembling a myeloproliferative syndrome. This syndrome was subsequently found to be independent of the BCG infection. Segregation analyses revealed that the myeloproliferative syndrome was controlled by a single recessive locus (Myls) mapping to a 9 megabases (Mb) region of chromosome 8. Myls contained one of the two replication-defective proviruses (Emv2) integrated into BXH-2 genome, and thought to play a role in generating the replication competent B-tropic ecotropic munne leukemia virus (MuLV) known to cause clonal tumours in BXH-2 mice. By narrowing down the Myls interval to 2 Mb, we could exclude Emv2 as a potential candidate for Myls. However, several other candidates remained, among which the interferon consensus sequence binding protein 1 (Icsbp1) gene. We showed that BXH-2 mice carry a mutation (915 C to T) resulting in an arginine-to-cysteine substitution at position 294 within the transactivation domain of the Icsbp1 protein. We found that Icsbp1C294 behaves as a hypomorphic allele which appears to have a threshold effect on maturation of the myeloid lineage, as well as pleiotropic consequences on resistance to different types of infectious agents including Mycobacterium bovis (BCG). Our results suggest a two-step mutagenic model in which first, inactivation of Icsbp1 predisposes to myeloproliferation and immunodeficiency and favours the production of retroviruses. Then, subsequent insertional mutagenesis of oncogenes or tumour suppressors by the retrovirus results in clonal expansion of leukemic cells characteristic of BXH-2 mice.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.103188 |
| Date | January 2006 |
| Creators | Turcotte, Karine. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Biochemistry.) |
| Rights | © Karine Turcotte, 2006 |
| Relation | alephsysno: 002585286, proquestno: AAINR32392, Theses scanned by UMI/ProQuest. |
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