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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2343-2350.
Prepublished online as a Blood First Edition Paper on November 20, 2003; DOI 10.1182/blood-2003-06-1852.
Submitted June 9, 2003
Accepted November 16, 2003
Genetic control of myeloproliferation in BXH-2 mice
Karine Turcotte, Susan Gauthier, Loukia-Maria Mitsos, Chaim Shustik, Neal G Copeland, Nancy A Jenkins, Jean-Christophe Fournet, Paul Jolicoeur, and Philippe Gros*
Department of Biochemistry, McGill University, Montreal, PQ, Canada
Department of Hematology, Royal Victoria Hospital, Montreal, PQ, Canada
Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA
Department of Pathology, Hopital Ste-Justine, Montreal, PQ, Canada
Department of Molecular Biology, Clinical Research Institute of Montreal, Montreal, PQ, Canada
Department of Experimental Medicine, McGill University, Montreal, PQ, Canada
Department of Microbiology & Immunology, Universite de Montreal, Montreal, PQ, Canada
* Corresponding author; email: philippe.gros{at}mcgill.ca.
While studying the unique Nramp1 (Slc11a1)-independent susceptibility to M. bovis (BCG) infection of BXH-2 mice, we noted that these mice develop important splenomegaly and enlargement of lymph nodes. Segregation analyses in several F2 crosses showed that splenomegaly segregates as a single recessive trait caused by a novel mutation in BXH-2, independent of the infection. Histological and FACS analyses indicated that splenomegaly is associated with a large increase in Mac1+/GR1+ granulocyte precursors in spleen, lymph nodes and bone marrow resembling a myeloproliferative syndrome. This is concomitant to extramedullary erythropoiesis in the spleen, as measured by proportion of Ter119+ erythroid cells. The locus controlling this myeloproliferative syndrome and splenomegaly was designated Myls and maps to an 18cM region of chromosome 8, which also contains an integrated copy of an N-ecotropic MuLV provirus (Emv2). The relationship between Myls, expansion of Mac1+/GR1+ cells and Emv2 was investigated. Homozygosity at Myls is necessary but not sufficient for B-ecotropic virus replication in splenocytes, the extent of which appears to be under separate genetic control. Our results suggest a model in which Myls-dependent myeloproliferation in BXH-2 acts as a predisposing factor for the subsequent development of virally-induced myeloid leukemia characteristic of this strain.
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