Proteinase-Activated Receptor 1 (PAR1) Regulates Leukemic Stem Cell Functions |
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| Authors: | Nicole B?umer Annika Krause Gabriele K?hler Stephanie Lettermann Georg Evers Antje Hascher Sebastian B?umer Wolfgang E. Berdel Carsten Müller-Tidow Lara Tickenbrock |
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| Affiliation: | 1. Department of Medicine, Hematology/Oncology, University of Muenster, Muenster, Germany.; 2. Gerhard Domagk Institute for Pathology, University of Muenster, Muenster, Germany.; 3. Interdisciplinary Center for Clinical Research IZKF, University of Muenster, Muenster, Germany.; 4. Dept. of Medicine IV, Hematology and Oncology, University of Halle, Halle, Germany.; 5. Hochschule Hamm-Lippstadt, University of Applied Science, Hamm, Germany.; RWTH Aachen University Medical School, Germany, |
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| Abstract: | External signals that are mediated by specific receptors determine stem cell fate. The thrombin receptor PAR1 plays an important role in haemostasis, thrombosis and vascular biology, but also in tumor biology and angiogenesis. Its expression and function in hematopoietic stem cells is largely unknown. Here, we analyzed expression and function of PAR1 in primary hematopoietic cells and their leukemic counterparts. AML patients'' blast cells expressed much lower levels of PAR1 mRNA and protein than CD34+ progenitor cells. Constitutive Par1-deficiency in adult mice did not affect engraftment or stem cell potential of hematopoietic cells. To model an AML with Par1-deficiency, we retrovirally introduced the oncogene MLL-AF9 in wild type and Par1−/− hematopoietic progenitor cells. Par1-deficiency did not alter initial leukemia development. However, the loss of Par1 enhanced leukemic stem cell function in vitro and in vivo. Re-expression of PAR1 in Par1−/− leukemic stem cells delayed leukemogenesis in vivo. These data indicate that Par1 contributes to leukemic stem cell maintenance. |
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