1. AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/β-catenin signaling pathway.
- Author
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Zhang Y, Wang J, Wheat J, Chen X, Jin S, Sadrzadeh H, Fathi AT, Peterson RT, Kung AL, Sweetser DA, and Yeh JR
- Subjects
- Animals, Core Binding Factor Alpha 2 Subunit genetics, Cyclooxygenase 2 genetics, Cyclooxygenase Inhibitors pharmacology, Gene Expression Regulation, Enzymologic drug effects, Gene Expression Regulation, Enzymologic genetics, Gene Expression Regulation, Leukemic drug effects, Gene Expression Regulation, Leukemic genetics, Hematopoietic Stem Cells pathology, Humans, K562 Cells, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Mice, Mice, Transgenic, Neoplasm Transplantation, Neoplastic Stem Cells pathology, Oncogene Proteins, Fusion genetics, RUNX1 Translocation Partner 1 Protein, Sulfonamides pharmacology, Transplantation, Heterologous, Zebrafish, beta Catenin genetics, Cell Proliferation, Core Binding Factor Alpha 2 Subunit metabolism, Cyclooxygenase 2 biosynthesis, Hematopoietic Stem Cells metabolism, Leukemia, Myeloid, Acute metabolism, Neoplastic Stem Cells metabolism, Oncogene Proteins, Fusion metabolism, Signal Transduction, beta Catenin metabolism
- Abstract
Developing novel therapies that suppress self-renewal of leukemia stem cells may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase (COX)-2 and β-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. Inhibition of COX suppresses β-catenin activation and serial replating of AE(+) mouse HSPCs. Genetic knockdown of β-catenin also abrogates the clonogenic growth of AE(+) mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/β-catenin-dependent signaling pathway in tumor initiation, growth, and self-renewal, and in providing the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments.
- Published
- 2013
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