Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia

• Published in: Oncogene Vol. 36; no. 18; pp. 2589 - 2598
• Main Authors: Goyama, S, Shrestha, M, Schibler, J, Rosenfeldt, L, Miller, W, O’Brien, E, Mizukawa, B, Kitamura, T, Palumbo, J S, Mulloy, J C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.05.2017; Nature Publishing Group
• Subjects: 631/67/1990/283/1897; 631/67/71; Acute myelocytic leukemia; Acute myeloid leukemia; AML1 protein; Animals; Apoptosis; Biomarkers; Bone marrow; c-Kit protein; Care and treatment; Cell Biology; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Core Binding Factor Alpha 2 Subunit - genetics; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Development and progression; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Genetic aspects; Hemostasis; Human Genetics; Humans; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Leukemogenesis; Leukemogenicity; Medicine; Medicine & Public Health; Mice; Neoplastic Stem Cells - pathology; Oncology; original-article; Pathogenesis; Physiological aspects; Proteases; Proteinase-activated receptor 1; Receptor, PAR-1 - biosynthesis; Receptor, PAR-1 - genetics; Runx1 protein; Stem cells; Thrombin; Transplantation; United States; Japan
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.416

Eradication of leukemia stem cells (LSCs) is the ultimate goal of treating acute myeloid leukemia (AML). We recently showed that the combined loss of Runx1/Cbfb inhibited the development of MLL-AF9-induced AML. However, c-Kit + /Gr-1 − cells remained viable in Runx1/Cbfb -deleted cells, indicating that suppressing RUNX activity may not eradicate the most immature LSCs. In this study, we found upregulation of several hemostasis-related genes, including the thrombin-activatable receptor PAR-1 (protease-activated receptor-1), in Runx1/Cbfb -deleted MLL-AF9 cells. Similar to the effect of Runx1/Cbfb deletion, PAR-1 overexpression induced CDKN1A/p21 expression and attenuated proliferation in MLL-AF9 cells. To our surprise, PAR-1 deficiency also prevented leukemia development induced by a small number of MLL-AF9 leukemia stem cells (LSCs) in vivo . PAR-1 deficiency also reduced leukemogenicity of AML1-ETO-induced leukemia. Re-expression of PAR-1 in PAR-1-deficient cells combined with a limiting-dilution transplantation assay demonstrated the cell-dose-dependent role of PAR-1 in MLL-AF9 leukemia: PAR-1 inhibited rapid leukemic proliferation when there were a large number of LSCs, while a small number of LSCs required PAR-1 for their efficient growth. Mechanistically, PAR-1 increased the adherence properties of MLL-AF9 cells and promoted their engraftment to bone marrow. Taken together, these data revealed a multifaceted role for PAR-1 in leukemogenesis, and highlight this receptor as a potential target to eradicate primitive LSCs in AML.