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Blood, 15 September 2005, Vol. 106, No. 6, pp. 2120-2127.
Prepublished online as a Blood First Edition Paper on June 7, 2005; DOI 10.1182/blood-2004-12-4969.
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Submitted January 3, 2005
Accepted April 29, 2005
Motility, proliferation and egress to the circulation of human AML cells in transplanted NOD/SCID mice are elastase dependent
Sigal Tavor, Isabelle Petit, Svetlana Porozov, Polina Goichberg, Abraham Avigdor, Sari Sagiv, Arnon Nagler, Elizabeth Naparstek, and Tsvee Lapidot*
Immunology Department, Weizmann Institute of Science, Rehovot, Israel; Department of Hematology and BMT, Sourasky Medical Center, Tel Aviv, Israel
Immunology Department, Weizmann Institute of Science, Rehovot, Israel
Immunology Department, Weizmann Institute of Science, Rehovot, Israel; Institute of Hematology, Sheba Medical Center, Tel-Hashomer, Israel
Institute of Hematology, Sheba Medical Center, Tel-Hashomer, Israel
Department of Hematology and BMT, Sourasky Medical Center, Tel Aviv, Israel
* Corresponding author; email: Tsvee.Lapidot{at}weizmann.ac.il.
The role of the proteolytic enzyme elastase in motility and proliferation of leukemic human AML cells is currently unknown. We report a correlation between abnormal high levels of elastase in the blood of AML patients and the number of leukemic blast cells in the circulation. In AML cells, we observed expression of cell surface elastase, which was regulated by the chemokine SDF-1. In vitro inhibition of elastase prevented SDF-1-induced cell polarization, podia formation and reduced migration of human AML cells as well as their adhesion. Elastase inhibition also significantly impaired in vivo homing of most human AML cells to the BM of transplanted NOD/SCID/B2mnull mice. Moreover, in vitro proliferation of AML cells was elastase-dependent. In contrast, treatment with elastase inhibitor enhanced the proliferation rate of human cord blood CD34+ cells, including primitive CD34+/38- cells, and their in vivo homing. Finally, NOD/SCID mice previously engrafted with human AML cells and treated with elastase inhibitor had significantly reduced egress of leukemic cells into the circulation. Taken together our data demonstrate that human AML cells constitutively secrete and express SDF-1 dependent cell surface elastase, which regulates their migration and proliferation.
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