AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/beta-catenin signaling pathway
- Authors
- Zhang, Y., Wang, J., Wheat, J., Chen, X., Jin, S., Sadrzadeh, H., Fathi, A.T., Peterson, R.T., Kung, A.L., Sweetser, D.A., and Yeh, J.R.
- ID
- ZDB-PUB-130607-6
- Date
- 2013
- Source
- Blood 121(24): 4906-16 (Journal)
- Registered Authors
- Peterson, Randall, Yeh, Jing-Ruey (Joanna)
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Proliferation*
- Core Binding Factor Alpha 2 Subunit/genetics
- Core Binding Factor Alpha 2 Subunit/metabolism*
- Cyclooxygenase 2/biosynthesis*
- 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/metabolism*
- Hematopoietic Stem Cells/pathology
- Humans
- K562 Cells
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism*
- Leukemia, Myeloid, Acute/pathology
- Mice
- Mice, Transgenic
- Neoplasm Transplantation
- Neoplastic Stem Cells/metabolism*
- Neoplastic Stem Cells/pathology
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism*
- Signal Transduction*
- Sulfonamides/pharmacology
- Transplantation, Heterologous
- Zebrafish
- beta Catenin/genetics
- beta Catenin/metabolism*
- PubMed
- 23645839 Full text @ Blood
Developing novel therapies that suppress self-renewal of leukemia stem cells (LSCs) 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 LSCs. 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-2 (COX-2) and β-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox2 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 provide the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments.