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. (2013) AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/beta-catenin signaling pathway. Blood. 121(24):4906-16.
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.