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ZIRC
ZFIN ID: ZDB-PUB-130607-6
AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/beta-catenin signaling pathway
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.
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
ABSTRACT

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.

ADDITIONAL INFORMATION No data available