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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1306-1313.
Prepublished online as a Blood First Edition Paper on May 11, 2004; DOI 10.1182/blood-2004-04-1522.
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Submitted April 23, 2004
Accepted April 24, 2004
Synergystic Effects on Erythropoiesis, Thrombopoiesis and Stem Cell Competitiveness in Mice Deficient for Thrombopoietin and Steel Factor Receptors
Jennifer Antonchuk, Craig D Hyland, Douglas J Hilton, and Warren S Alexander*
Cancer & Haematology Division, Walter & Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
* Corresponding author; email: alexandw{at}wehi.edu.au.
The degree of redundancy between thrombopoietin (Tpo) and steel factor (SF) cytokine pathways in the regulation of hematopoiesis was investigated by generating mice lacking both c-Mpl and fully functional c-Kit receptors. Double mutant c-Mpl-/-;KitWv/Wv mice exhibited reduced viability, making up only 2% of the offspring from c-Mpl-/-;KitWv/+ intercrosses. The thrombocytopenia and megakaryocytopenia characteristic of c-Mpl-/- mice was unchanged in c-Mpl-/-;KitWv/Wv mice. However, the number of megakaryocytic colony forming units (CFU-Mk) was significantly reduced, particularly in the spleen. While KitWv/Wv mice, but not c-Mpl-/- mice, are anaemic, the anaemia was more severe in double mutant c-Mpl-/-;KitWv/Wv mice, indicating redundancy between Tpo and SF in erythropoiesis. At the primitive cell level, c-Mpl-/- and KitWv/Wv mice have similar phenotypes, including reduced progenitors, colony forming units-spleen (CFU-S), and repopulating activities. All of these parameters were exacerbated in double mutant mice. c-Mpl-/-;KitWv/Wv mice had 8-fold fewer clonogenic progenitor cells and at least 28-fold fewer CFU-S. c-Mpl-/- mice also demonstrated a reduced threshold requirement for non-myeloablative transplant repopulation, a trait previously associated only with KitW mice, and the level of non-myeloablative engraftment was significantly greater in c-Mpl-/-;KitWv/Wv double mutants. Thus, c-Mpl-/-;KitWv/Wv mice reveal non-redundant and synergistic effects of Tpo and SF on primitive hematopoietic cells.
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