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 Blood, 27 August 2009, Vol. 114, No. 9, pp. 1831-1841.
Prepublished online as a Blood First Edition Paper on July 7, 2009; DOI 10.1182/blood-2008-11-187419.

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MYELOID NEOPLASIA

Enrichment of Sca1+ hematopoietic progenitors in polycythemic mice inhibits leukemogenesis

Tatiana Usenko1, You-Jun Li1, Mehran Haeri1,2, Yanmei Li1, Laura M. Vecchiarelli-Federico1,2, Xiaojun Zhao1, Josef T. Prchal3, and Yaacov Ben-David1,2

1 Molecular and Cellular Biology, Sunnybrook Health Sciences Centre, Toronto, ON; 2 Department of Medical Biophysics, University of Toronto, Toronto, ON; and 3 Division of Hematology, School of Medicine, University of Utah, Salt Lake City

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 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 cotransplantation 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 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.


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