Submitted November 3, 2008
Accepted May 29, 2009
Enrichment of SCA1 positive hematopoietic progenitors in polycythemic mice inhibits leukemogenesis
Tatiana Usenko, You-Jun Li, Mehran Haeri, Yanmei Li, Laura M. Vecchiarelli-Federico, Xiaojun Zhao, Josef T Prchal, and Yaacov Ben-David*
Molecular and Cellular Biology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT, United States
* Corresponding author; email: bendavid{at}sri.utoronto.ca.
Polycythemia vera (PV) is a myeloproliferative disorder characterized by a pronounced increase in the number of erythroid cells. However, despite this aberrant proliferation, the incidence of erythroleukemia is paradoxically rare in PV patients. In this study, we show that the progression of Friend virus-induced erythroleukemia is delayed in a mouse model of primary familial congenital polycythemia (PFCP) in which the wild-type Epo-receptor (EpoR) gene is replaced with a truncated human EPOR gene. Herein, we show that these mice exhibit enrichment of Sca1+/cKit- progenitors and several mature immune cells such as dendritic cells and macrophages. In co-transplantation experiments, Sca1+/cKit- progenitors inhibit the tumorigenicity of Sca1-/cKit+ erythroleukemic cells. A cell line established from Sca1+/cKit- progenitors is also capable of inhibiting leukemic proliferation in culture and in mice. This phenomenon of leukemic inhibition, also detected in the serum of PV patients, is partially attributed to increased nitric oxide (NO) secretion. In addition, the administration of erythropoietin into leukemic mice induces a polycythemia-like state associated with the expansion of Sca1+/cKit- progenitors and derivative immune cells thereby inhibiting leukemia progression. This study indicates that a combination therapy incorporating the enrichment of Sca1+/cKit- progenitors may serve as a novel approach for the treatment of leukemia.
